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Kouroumalis E, Tsomidis I, Voumvouraki A. HFE-Related Hemochromatosis May Be a Primary Kupffer Cell Disease. Biomedicines 2025; 13:683. [PMID: 40149659 PMCID: PMC11940282 DOI: 10.3390/biomedicines13030683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/28/2025] [Accepted: 03/08/2025] [Indexed: 03/29/2025] Open
Abstract
Iron overload can lead to increased deposition of iron and cause organ damage in the liver, the pancreas, the heart and the synovium. Iron overload disorders are due to either genetic or acquired abnormalities such as excess transfusions or chronic liver diseases. The most common genetic disease of iron deposition is classic hemochromatosis (HH) type 1, which is caused by mutations of HFE. Other rare forms of HH include type 2A with mutations at the gene hemojuvelin or type 2B with mutations in HAMP that encodes hepcidin. HH type 3, is caused by mutations of the gene that encodes transferrin receptor 2. Mutations of SLC40A1 which encodes ferroportin cause either HH type 4A or HH type 4B. In the present review, an overview of iron metabolism including absorption by enterocytes and regulation of iron by macrophages, liver sinusoidal endothelial cells (LSECs) and hepatocyte production of hepcidin is presented. Hereditary Hemochromatosis and the current pathogenetic model are analyzed. Finally, a new hypothesis based on published data was suggested. The Kupffer cell is the primary defect in HFE hemochromatosis (and possibly in types 2 and 3), while the hepcidin-relative deficiency, which is the common underlying abnormality in the three types of HH, is a secondary consequence.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, PAGNI University Hospital, University of Crete Medical School, 71500 Heraklion, Greece
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Greece;
| | - Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Greece;
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece;
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Huang L, Lai HJ, Furuya KN, Antos NJ, Asfour F, Boyne KL, Howenstine M, Rock MJ, Sawicki GS, Gaffin JM, Worthey EA, Farrell PM. The Frequency and Potential Implications of HFE Genetic Variants in Children With Cystic Fibrosis. Pediatr Pulmonol 2025; 60:e71042. [PMID: 40071665 PMCID: PMC11898569 DOI: 10.1002/ppul.71042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 02/24/2025] [Accepted: 03/01/2025] [Indexed: 03/15/2025]
Abstract
BACKGROUND Genetic modifiers have been identified that increase the risks of lung disease and other complications, such as diabetes in people with cystic fibrosis (CF). Variants in the hemochromatosis gene (HFE) were reported in a study of adults to be associated with worse lung disease. OBJECTIVES To ascertain the frequency of HFE variants, particularly C282Y (c.845G > A) and H63D (c.187C > G) and to determine if they are associated with variations in the onset and early severity of CF lung disease as well as abnormalities in iron status. DESIGN We studied with whole genome sequencing and clinical outcome measures in a cohort of 104 children with CF at 5-6 years old who were previously found to show an association between aggregated genetic modifiers and an earlier onset and a more severe lung disease phenotype. RESULTS In our cohort, 23% have H63D and 11% have C282Y. Lung function at age 6 years and Pseudomonas aeruginosa infections did not differ by HFE variants, but having C282Y was associated with more pulmonary exacerbations in the first 6 years of life. Three patients have H63D/C282Y genotype, and all showed phenotypic expression of hemochromatosis with abnormal iron indices. CONCLUSION Our study revealed that the presence of HFE variant C282Y in people with CF may lead to more severe lung disease manifestations beginning in early childhood. There is a risk of hemochromatosis in CF patients with two HFE variants, and thus they should be followed for evidence of iron overload.
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Affiliation(s)
- Leslie Huang
- Department of PediatricsUniversity of Wisconsin – MadisonMadisonWisconsinUSA
| | - HuiChuan J. Lai
- Department of PediatricsUniversity of Wisconsin – MadisonMadisonWisconsinUSA
- Department of Nutritional SciencesUniversity of Wisconsin – MadisonMadisonWisconsinUSA
| | - Katryn N. Furuya
- Department of PediatricsUniversity of Wisconsin – MadisonMadisonWisconsinUSA
| | - Nicholas J. Antos
- Department of PediatricsMedical College of WisconsinMilwaukeeWisconsinUSA
| | - Fadi Asfour
- Department of PediatricsUniversity of UtahSalt Lake CityUtahUSA
| | | | | | - Michael J. Rock
- Department of PediatricsUniversity of Wisconsin – MadisonMadisonWisconsinUSA
| | - Gregory S. Sawicki
- Department of PediatricsBoston Children's HospitalBostonMassachusettsUSA
| | - Jonathan M. Gaffin
- Department of PediatricsBoston Children's HospitalBostonMassachusettsUSA
| | | | - Philip M. Farrell
- Department of PediatricsUniversity of Wisconsin – MadisonMadisonWisconsinUSA
- Department of Population Health SciencesUniversity of Wisconsin – MadisonMadisonWisconsinUSA
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Ishikawa T, Tatsumi Y, Kato K, Hayashi Y, Imai N, Ito T, Ishizu Y, Ishigami M, Nihei W, Kato A, Hayashi H. A 70-year-old Woman with Asymptomatic Ferroportin Disease. Intern Med 2024; 63:2421-2425. [PMID: 38296485 PMCID: PMC11442921 DOI: 10.2169/internalmedicine.2392-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 11/21/2023] [Indexed: 09/03/2024] Open
Abstract
A 59-year-old Japanese woman presented with hyperferritinemia. We decided against iron removal treatment because there were no symptoms or signs of iron-induced organ damage. A follow-up study revealed a gradual increase in transferrin saturation. The patient underwent a second examination at 66 years old. A liver biopsy showed substantial iron deposits in hepatocytes and Kupffer cells but no inflammation or fibrosis. Serum hepcidin-25 levels were highly parallel with hyperferritinemia. A genetic analysis revealed a G80S mutation in SLC40A1. These features are compatible with those of ferroportin disease. The patient remained asymptomatic at 70 years old, suggesting that the iron-loading condition may have been benign.
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Affiliation(s)
- Tetsuya Ishikawa
- Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Japan
| | - Yasuaki Tatsumi
- Department of Medical Biochemistry, Faculty of Pharmaceutical Sciences, Toho University, Japan
| | - Koichi Kato
- Department of Medicine, Aichi Gakuin University School of Pharmacy, Japan
| | - Yumi Hayashi
- Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Japan
| | - Norihiro Imai
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Japan
| | - Takanori Ito
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Japan
| | - Yoji Ishizu
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Japan
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Japan
| | - Wataru Nihei
- Department of Medicine, Aichi Gakuin University School of Pharmacy, Japan
| | - Ayako Kato
- Department of Medicine, Aichi Gakuin University School of Pharmacy, Japan
| | - Hisao Hayashi
- Department of Medicine, Aichi Gakuin University School of Pharmacy, Japan
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Zhang X, Hu X, Fang S, Li J, Liu Z, Xie W, Xu R, Dmytriw AA, Yang K, Ma Y, Jiao L, Wang T. Vascular Endothelial Growth Factor and Ischemic Stroke Risk: A Mendelian Randomization Study. Neurol Ther 2024; 13:727-737. [PMID: 38619804 PMCID: PMC11136897 DOI: 10.1007/s40120-024-00601-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 03/07/2024] [Indexed: 04/16/2024] Open
Abstract
INTRODUCTION Previous studies have reported controversial relationships between circulating vascular endothelial growth factors (VEGF) and ischemic stroke (IS). This study aims to demonstrate the causal effect between VEGF and IS using Mendelian randomization (MR). METHODS Summary statistics data from two large-scale genome-wide association studies (GWAS) for 16,112 patients with measured VEGF levels and 40,585 patients with IS were downloaded from public databases and included in this study. A published calculator was adopted for MR power calculation. The primary outcome was any ischemic stroke, and the secondary outcomes were large-artery stroke, cardioembolic stroke, and small-vessel stroke. We used the inverse variance-weighted (IVW) method for primary analysis, supplemented by MR-Egger regression and the weighted median method. RESULTS Nine SNPs were included to represent serum VEGF levels. The IVW method revealed no strong causal association between VEGF and any ischemic stroke (odds ratio [OR] 1.01, 95% CI 0.99-1.04, p = 0.39), cardioembolic stroke (OR 1.04, 95% CI 0.97-1.12, p = 0.28), large-artery stroke (OR 1.02, 95% CI 0.95-1.09, p = 0.62), and small-vessel stroke (OR 0.98, 95% CI 0.91-1.04, p = 0.46). These findings remained robust in sensitivity analyses. MR-Egger regression suggested no horizontal pleiotropy. CONCLUSIONS This Mendelian randomization study found no relationship between genetically predisposed serum VEGF levels and risks of IS or its subtypes.
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Affiliation(s)
- Xiao Zhang
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, 100053, China
- Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK
- China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, 100053, China
| | - Xinzhi Hu
- Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Shiyuan Fang
- Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, 100730, China
- Department of Neurology, Peking Union Medical College Hospital, Beijing, 100730, China
| | - Jiayao Li
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, 100053, China
- China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, 100053, China
| | - Zhichao Liu
- Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK
| | - Weidun Xie
- Department of Computer Science, City University of Hong Kong, Kowloon, 999077, Hong Kong SAR
| | - Ran Xu
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, 100053, China
- China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, 100053, China
| | - Adam A Dmytriw
- Neuroendovascular Program, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Kun Yang
- Department of Neurosurgery, Tai'an Central Hospital, 29 Longtan Road, Tai'an, 271000, Shandong, China
| | - Yan Ma
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, 100053, China
- China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, 100053, China
| | - Liqun Jiao
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, 100053, China.
- China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, 100053, China.
- Department of Interventional Neuroradiology, Xuanwu Hospital, Capital Medical University, No. 45 Changchun Street, Xicheng District Beijing, 100053, China.
| | - Tao Wang
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, 100053, China.
- China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, 100053, China.
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Naelitz BD, Khooblall PS, Parekh NV, Vij SC, Rotz SJ, Lundy SD. The effect of red blood cell disorders on male fertility and reproductive health. Nat Rev Urol 2024; 21:303-316. [PMID: 38172196 DOI: 10.1038/s41585-023-00838-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/10/2023] [Indexed: 01/05/2024]
Abstract
Male infertility is defined as a failure to conceive after 12 months of unprotected intercourse owing to suspected male reproductive factors. Non-malignant red blood cell disorders are systemic conditions that have been associated with male infertility with varying severity and strength of evidence. Hereditary haemoglobinopathies and bone marrow failure syndromes have been associated with hypothalamic-pituitary-gonadal axis dysfunction, hypogonadism, and abnormal sperm parameters. Bone marrow transplantation is a potential cure for these conditions, but exposes patients to potentially gonadotoxic chemotherapy and/or radiation that could further impair fertility. Iron imbalance might also reduce male fertility. Thus, disorders of hereditary iron overload can cause iron deposition in tissues that might result in hypogonadism and impaired spermatogenesis, whereas severe iron deficiency can propagate anaemias that decrease gonadotropin release and sperm counts. Reproductive urologists should be included in the comprehensive care of patients with red blood cell disorders, especially when gonadotoxic treatments are being considered, to ensure fertility concerns are appropriately evaluated and managed.
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Affiliation(s)
- Bryan D Naelitz
- Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
| | - Prajit S Khooblall
- Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Neel V Parekh
- Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Sarah C Vij
- Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Seth J Rotz
- Department of Paediatric Hematology and Oncology, Cleveland Clinic Children's Hospital, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Scott D Lundy
- Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
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Tatsumi Y, Yano M, Wakusawa S, Miyajima H, Ishikawa T, Imashuku S, Takano A, Nihei W, Kato A, Kato K, Hayashi H, Yoshioka K, Hayashi K. A Revised Classification of Primary Iron Overload Syndromes. J Clin Transl Hepatol 2024; 12:346-356. [PMID: 38638373 PMCID: PMC11022062 DOI: 10.14218/jcth.2023.00290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 11/02/2023] [Accepted: 12/11/2023] [Indexed: 04/20/2024] Open
Abstract
Background and Aims The clinical introduction of hepcidin25 (Hep25) has led to a more detailed understanding of its relationship with ferroportin (FP) and divalent metal transporter1 in primary iron overload syndromes (PIOSs). In 2012, we proposed a classification of PIOSs based on the Hep25/FP system, which consists of prehepatic aceruloplasminemia, hepatic hemochromatosis (HC), and posthepatic FP disease (FP-D). However, in consideration of accumulated evidence on PIOSs, we aimed to renew the classification. Methods We reviewed the 2012 classification and retrospectively renewed it according to new information on PIOSs. Results Iron-loading anemia was included in PIOSs as a prehepatic form because of the newly discovered erythroferrone-induced suppression of Hep25, and the state of traditional FP-D was remodeled as the BIOIRON proposal. The key molecules responsible for prehepatic PIOSs are low transferrin saturation in aceruloplasminemia and increased erythroferrone production by erythroblasts in iron-loading anemia. Hepatic PIOSs comprise four genotypes of HC, in each of which the synthesis of Hep25 is inappropriately reduced in the liver. Hepatic Hep25 synthesis is adequate in posthepatic PIOSs; however, two mutant FP molecules may resist Hep25 differently, resulting in SLC40A1-HC and FP-D, respectively. PIOS phenotypes are diagnosed using laboratory tests, including circulating Hep25, followed by suitable treatments. Direct sequencing of the candidate genes may be outsourced to gene centers when needed. Laboratory kits for the prevalent mutations, such as C282Y, may be the first choice for a genetic analysis of HC in Caucasians. Conclusions The revised classification may be useful worldwide.
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Affiliation(s)
- Yasuaki Tatsumi
- Department of Medical Biochemistry, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Japan
| | - Motoyoshi Yano
- Department of Gastroenterology, Yokkaichi Municipal Hospital, Yokkaichi, Japan
| | - Shinya Wakusawa
- Department of Medical Technology, Shubun University, Ichinomiya, Japan
| | - Hiroaki Miyajima
- Department of Medicine and Neurology, Tenryu Kohseikai Clinic, Hamamatsu, Japan
| | - Tetsuya Ishikawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shinsaku Imashuku
- Department of Laboratory Medicine, Uji-Tokushukai Medical Center, Uji, Japan
| | - Atsuko Takano
- Department of Medicine, Saiseikai Takaoka Hospital, Takaoka, Japan
| | - Wataru Nihei
- Department of Medicine, Aichi-Gakuin University School of Pharmacy, Nagoya, Japan
| | - Ayako Kato
- Department of Medicine, Aichi-Gakuin University School of Pharmacy, Nagoya, Japan
| | - Koichi Kato
- Department of Medicine, Aichi-Gakuin University School of Pharmacy, Nagoya, Japan
| | - Hisao Hayashi
- Department of Medicine, Aichi-Gakuin University School of Pharmacy, Nagoya, Japan
| | - Kentaro Yoshioka
- Department of Gastroenterology, FNPS Meijo Hospital, Nagoya, Japan
| | - Kazuhiko Hayashi
- Department of Gastroenterology, FNPS Meijo Hospital, Nagoya, Japan
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Sohal A, Kowdley KV. A Review of New Concepts in Iron Overload. Gastroenterol Hepatol (N Y) 2024; 20:98-107. [PMID: 38414914 PMCID: PMC10895914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/29/2024]
Abstract
Iron overload disorders are conditions that can lead to increased body iron stores and end-organ damage in affected organs. Increased iron deposition most commonly occurs in the liver, heart, endocrine system, joints, and pancreas. Iron overload disorders may be caused by genetic or acquired causes (transfusion, dyserythropoiesis, and chronic liver disease). The HFE gene C282Y homozygous mutation is the most common cause of hereditary hemochromatosis (HH). Other genes implicated in HH include TFR2, HAMP, HJV, and SLC40A1. In the past 2 decades, there have been major advances in the understanding of genetic iron overload disorders. Furthermore, new novel techniques to measure iron content in organs noninvasively, as well as new therapeutic options for the treatment of HH, are currently under development. This article focuses on the latest concepts in understanding, diagnosing, and managing genetic iron overload disorders, particularly HH.
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Affiliation(s)
- Aalam Sohal
- Liver Institute Northwest, Seattle, Washington
| | - Kris V Kowdley
- Liver Institute Northwest, Seattle, Washington
- Elson S. Floyd College of Medicine, Washington State University, Spokane, Washington
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Yerigeri K. Hemochromatosis in an Adult Female With Previous Iron Deficiency Anemia on Iron Supplementation. Cureus 2023; 15:e50166. [PMID: 38186413 PMCID: PMC10771745 DOI: 10.7759/cureus.50166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/08/2023] [Indexed: 01/09/2024] Open
Abstract
A 56-year-old female presented with a diagnosis of iron deficiency anemia over three years prior (on oral iron supplementation) and presented with altered mental status. She was admitted to the Coronary Care Unit for troponinemia and T-wave inversions. Two-dimensional echocardiography revealed hypokinesia of the left ventricle (LV) anterior wall with reduced ejection fraction. The patient was stabilized on metoprolol and heparin infusions, but heparin was discontinued after iron studies revealed overload (iron: 159 ug/dL, 100% saturation, ferritin: 1480 ng/mL). Cardiac MRI revealed mixed concentric-eccentric LV hypertrophy, raising concern for severe iron overload. Mutation analysis of the HFE (homeostatic iron regulator) gene responsible for hereditary hemochromatosis was negative for a homozygous mutation. Hematology was consulted to establish outpatient follow-up and consider treatments for the acquired hemochromatosis. Acquired hemochromatosis typically occurs in the setting of multiple blood product transfusions. Oral supplementation is typically mitigated by limited bioavailability. Follow-up was needed to track the patient's iron deficiency anemia and identify resolution and potential toxicity. Further research into predisposing factors for hemochromatosis in patients on oral supplementation without HFE mutations is indicated.
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Affiliation(s)
- Keval Yerigeri
- Internal Medicine-Pediatrics, Case Western Reserve University School of Medicine, Cleveland, USA
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9
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Barton JC, Edwards CQ, Acton RT. HFE hemochromatosis in African Americans: Prevalence estimates of iron overload and iron overload-related disease. Am J Med Sci 2023; 365:31-36. [PMID: 36096187 DOI: 10.1016/j.amjms.2022.08.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 05/03/2022] [Accepted: 08/10/2022] [Indexed: 01/12/2023]
Abstract
BACKGROUND Little is known about the prevalence of HFE (homeostatic iron regulator) hemochromatosis in African Americans (AA). METHODS We defined AA as self-identified AA, blacks, or non-Hispanic blacks. We defined hemochromatosis-associated HFE genotypes as p.C282Y/p.C282Y and p.C282Y/p.H63D. We compiled prevalences of these genotypes in AA using published population and cohort data and numbers of men and women ≥18 y in 2018 U.S. Census estimates. We defined iron overload (IO) and IO-related disease by genotype as previously reported in population and cohort studies of hemochromatosis in whites of European ancestry. We used these definitions to estimate prevalences and numbers of AA with IO and IO-related disease associated with hemochromatosis-associated HFE genotypes. RESULTS There were ∼16,287,599 men and ∼17,644,898 women. HFE genotypes and their respective prevalences were: p.C282Y/p.C282Y, 0.00017 (6/34,905) [95% confidence interval 0.000034, 0.00031] and p.C282Y/p.H63D, 0.0012 (41/33,596) [0.000084, 0.0016]. IO prevalences were: men 0.000076 [0.000072, 0.000081] and women 0.0000061 [0.0000050, 0.0000073]. IO-related disease prevalences were: men 0.000063 [0.000059, 0.000067] and women 0.0000021 [0.0000014, 0.0000027]. There were ∼1021 [961, 1091] men and ∼36 [25, 48] women with IO-related disease. CONCLUSIONS We conclude that ∼1/25,061 AA >18 y have a hemochromatosis-associated HFE genotype and IO and that ∼1/32,103 AA >18 y have a hemochromatosis-associated HFE genotype and IO-related disease.
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Affiliation(s)
- James C Barton
- Southern Iron Disorders Center, Birmingham, AL, USA; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
| | - Corwin Q Edwards
- Department of Medicine, Intermountain Medical Center and University of Utah, Salt Lake City, UT, USA
| | - Ronald T Acton
- Southern Iron Disorders Center, Birmingham, AL, USA; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA
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Left Ventricular Function and Iron Loading Status in a Tertiary Center Hemochromatosis Cohort-A Cardiac Magnetic Resonance Study. Diagnostics (Basel) 2022; 12:diagnostics12112620. [PMID: 36359463 PMCID: PMC9689750 DOI: 10.3390/diagnostics12112620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/18/2022] [Accepted: 10/24/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Haemochromatosis (HCH), a common genetic disorder with variable penetrance, results in progressive but understudied iron overload. We prospectively evaluated organ iron loading and cardiac function in a tertiary center HCH cohort. Methods: 42 HCH patients (47 ± 14 years) and 36 controls underwent laboratory workup and cardiac magnetic resonance (CMR), including T1 and T2* mapping. Results: Myocardial T2* (myoT2*), myocardial T1 (myoT1) and liver T2* (livT2*) were lower in patients compared to controls (33 ± 4 ms vs. 36 ± 3 ms [p = 0.004], 964 ± 33 ms vs. 979 ± 25 ms [p = 0.028] and 21 ± 10 ms vs. 30 ± 5 ms [p < 0.001], respectively). MyoT2* did not reach the threshold of clinically significant iron overload (<20 ms), in any of the patients. In 22 (52.4%) patients, at least one of the tissue parameters was reduced. Reduced myocardial T2* and/or T1 were found in 10 (23.8%) patients, including 4 pts with normal livT2*. LivT2* was reduced in 18 (42.9%) patients. MyoT1 and livT2* inversely correlated with ferritin (rs = −0.351 [p = 0.028] and rs = −0.602 [p < 0.001], respectively). LivT2* by a dedicated sequence and livT2* by cardiac T2* mapping showed good agreement (ICC = 0.876 p < 0.001). Conclusions: In contemporary hemochromatosis, significant myocardial iron overload is rare. Low myocardial T2* and/or T1 values may warrant closer follow-up for accelerated myocardial iron overload even in patients without overt liver overload. Cardiac T2* mapping sequence allows for liver screening at the time of CMR.
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Zheng M, Allington G, Vilarinho S. Genomic medicine for liver disease. Hepatology 2022; 76:860-868. [PMID: 35076957 PMCID: PMC10460497 DOI: 10.1002/hep.32364] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/13/2022] [Accepted: 01/18/2022] [Indexed: 12/08/2022]
Affiliation(s)
- Melanie Zheng
- Departments of Internal Medicine, Section of Digestive Diseases, and of Pathology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Garrett Allington
- Departments of Internal Medicine, Section of Digestive Diseases, and of Pathology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Sílvia Vilarinho
- Departments of Internal Medicine, Section of Digestive Diseases, and of Pathology, Yale School of Medicine, New Haven, Connecticut, USA
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12
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Topiwala A, Wang C, Ebmeier KP, Burgess S, Bell S, Levey DF, Zhou H, McCracken C, Roca-Fernández A, Petersen SE, Raman B, Husain M, Gelernter J, Miller KL, Smith SM, Nichols TE. Associations between moderate alcohol consumption, brain iron, and cognition in UK Biobank participants: Observational and mendelian randomization analyses. PLoS Med 2022; 19:e1004039. [PMID: 35834561 PMCID: PMC9282660 DOI: 10.1371/journal.pmed.1004039] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 06/01/2022] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Brain iron deposition has been linked to several neurodegenerative conditions and reported in alcohol dependence. Whether iron accumulation occurs in moderate drinkers is unknown. Our objectives were to investigate evidence in support of causal relationships between alcohol consumption and brain iron levels and to examine whether higher brain iron represents a potential pathway to alcohol-related cognitive deficits. METHODS AND FINDINGS Observational associations between brain iron markers and alcohol consumption (n = 20,729 UK Biobank participants) were compared with associations with genetically predicted alcohol intake and alcohol use disorder from 2-sample mendelian randomization (MR). Alcohol intake was self-reported via a touchscreen questionnaire at baseline (2006 to 2010). Participants with complete data were included. Multiorgan susceptibility-weighted magnetic resonance imaging (9.60 ± 1.10 years after baseline) was used to ascertain iron content of each brain region (quantitative susceptibility mapping (QSM) and T2*) and liver tissues (T2*), a marker of systemic iron. Main outcomes were susceptibility (χ) and T2*, measures used as indices of iron deposition. Brain regions of interest included putamen, caudate, hippocampi, thalami, and substantia nigra. Potential pathways to alcohol-related iron brain accumulation through elevated systemic iron stores (liver) were explored in causal mediation analysis. Cognition was assessed at the scan and in online follow-up (5.82 ± 0.86 years after baseline). Executive function was assessed with the trail-making test, fluid intelligence with puzzle tasks, and reaction time by a task based on the "Snap" card game. Mean age was 54.8 ± 7.4 years and 48.6% were female. Weekly alcohol consumption was 17.7 ± 15.9 units and never drinkers comprised 2.7% of the sample. Alcohol consumption was associated with markers of higher iron (χ) in putamen (β = 0.08 standard deviation (SD) [95% confidence interval (CI) 0.06 to 0.09], p < 0.001), caudate (β = 0.05 [0.04 to 0.07], p < 0.001), and substantia nigra (β = 0.03 [0.02 to 0.05], p < 0.001) and lower iron in the thalami (β = -0.06 [-0.07 to -0.04], p < 0.001). Quintile-based analyses found these associations in those consuming >7 units (56 g) alcohol weekly. MR analyses provided weak evidence these relationships are causal. Genetically predicted alcoholic drinks weekly positively associated with putamen and hippocampus susceptibility; however, these associations did not survive multiple testing corrections. Weak evidence for a causal relationship between genetically predicted alcohol use disorder and higher putamen susceptibility was observed; however, this was not robust to multiple comparisons correction. Genetically predicted alcohol use disorder was associated with serum iron and transferrin saturation. Elevated liver iron was observed at just >11 units (88 g) alcohol weekly c.f. <7 units (56 g). Systemic iron levels partially mediated associations of alcohol intake with brain iron. Markers of higher basal ganglia iron associated with slower executive function, lower fluid intelligence, and slower reaction times. The main limitations of the study include that χ and T2* can reflect changes in myelin as well as iron, alcohol use was self-reported, and MR estimates can be influenced by genetic pleiotropy. CONCLUSIONS To the best of our knowledge, this study represents the largest investigation of moderate alcohol consumption and iron homeostasis to date. Alcohol consumption above 7 units weekly associated with higher brain iron. Iron accumulation represents a potential mechanism for alcohol-related cognitive decline.
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Affiliation(s)
- Anya Topiwala
- Nuffield Department Population Health, Big Data Institute, University of Oxford, Oxford, United Kingdom
| | - Chaoyue Wang
- Wellcome Centre for Integrative Neuroimaging (WIN FMRIB), Oxford University, Oxford, United Kingdom
| | - Klaus P. Ebmeier
- Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, United Kingdom
| | - Stephen Burgess
- MRC Biostatistics Unit, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
- Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Steven Bell
- Department of Clinical Neurosciences, University of Cambridge, United Kingdom
| | - Daniel F. Levey
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States of America
- Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, United States of America
| | - Hang Zhou
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States of America
- Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, United States of America
| | - Celeste McCracken
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | | | - Steffen E. Petersen
- William Harvey Research Institute, NIHR Barts Biomedical Research Centre, Queen Mary University of London, Charterhouse Square, London, United Kingdom
- Barts Heart Centre, St Bartholomew’s Hospital, Barts Health NHS Trust, West Smithfield, London, United Kingdom
- Health Data Research UK, London, United Kingdom
- Alan Turing Institute, London, United Kingdom
| | - Betty Raman
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Masud Husain
- Wellcome Centre for Integrative Neuroimaging (WIN FMRIB), Oxford University, Oxford, United Kingdom
- Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom
- Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, United Kingdom
- Division of Clinical Neurology, John Radcliffe Hospital, Oxford University Hospitals Trust, Oxford, United Kingdom
| | - Joel Gelernter
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States of America
- Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, United States of America
| | - Karla L. Miller
- Wellcome Centre for Integrative Neuroimaging (WIN FMRIB), Oxford University, Oxford, United Kingdom
| | - Stephen M. Smith
- Wellcome Centre for Integrative Neuroimaging (WIN FMRIB), Oxford University, Oxford, United Kingdom
| | - Thomas E. Nichols
- Nuffield Department Population Health, Big Data Institute, University of Oxford, Oxford, United Kingdom
- Wellcome Centre for Integrative Neuroimaging (WIN FMRIB), Oxford University, Oxford, United Kingdom
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13
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El-Kassas M, Elbadry M. Hepatocellular Carcinoma in Africa: Challenges and Opportunities. Front Med (Lausanne) 2022; 9:899420. [PMID: 35814750 PMCID: PMC9263092 DOI: 10.3389/fmed.2022.899420] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 05/30/2022] [Indexed: 12/25/2022] Open
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14
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Shahandeh A, Bui BV, Finkelstein DI, Nguyen CTO. Effects of Excess Iron on the Retina: Insights From Clinical Cases and Animal Models of Iron Disorders. Front Neurosci 2022; 15:794809. [PMID: 35185447 PMCID: PMC8851357 DOI: 10.3389/fnins.2021.794809] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 12/17/2021] [Indexed: 01/19/2023] Open
Abstract
Iron plays an important role in a wide range of metabolic pathways that are important for neuronal health. Excessive levels of iron, however, can promote toxicity and cell death. An example of an iron overload disorder is hemochromatosis (HH) which is a genetic disorder of iron metabolism in which the body’s ability to regulate iron absorption is altered, resulting in iron build-up and injury in several organs. The retina was traditionally assumed to be protected from high levels of systemic iron overload by the blood-retina barrier. However, recent data shows that expression of genes that are associated with HH can disrupt retinal iron metabolism. Thus, the effects of iron overload on the retina have become an area of research interest, as excessively high levels of iron are implicated in several retinal disorders, most notably age–related macular degeneration. This review is an effort to highlight risk factors for excessive levels of systemic iron build-up in the retina and its potential impact on the eye health. Information is integrated across clinical and preclinical animal studies to provide insights into the effects of systemic iron loading on the retina.
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Affiliation(s)
- Ali Shahandeh
- Department of Optometry and Vision Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia
| | - Bang V. Bui
- Department of Optometry and Vision Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia
| | - David I. Finkelstein
- Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia
| | - Christine T. O. Nguyen
- Department of Optometry and Vision Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia
- *Correspondence: Christine T. O. Nguyen,
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15
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Cavezzi A, Menicagli R, Troiani E, Corrao S. COVID-19, Cation Dysmetabolism, Sialic Acid, CD147, ACE2, Viroporins, Hepcidin and Ferroptosis: A Possible Unifying Hypothesis. F1000Res 2022; 11:102. [PMID: 35340277 PMCID: PMC8921693 DOI: 10.12688/f1000research.108667.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/20/2022] [Indexed: 08/26/2024] Open
Abstract
Background: iron and calcium dysmetabolism, with hyperferritinemia, hypoferremia, hypocalcemia and anemia have been documented in the majority of COVID-19 patients at later/worse stages. Furthermore, complementary to ACE2, both sialic acid (SA) molecules and CD147 proved relevant host receptors for SARS-CoV-2 entry, which explains the viral attack to multiple types of cells, including erythrocytes, endothelium and neural tissue. Several authors advocated that cell ferroptosis may be the core and final cell degenerative mechanism. Methods: a literature research was performed in several scientific search engines, such as PubMed Central, Cochrane Library, Chemical Abstract Service. More than 500 articles were retrieved until mid-December 2021, to highlight the available evidence about the investigated issues. Results: based on COVID-19 literature data, we have highlighted a few pathophysiological mechanisms, associated with virus-based cation dysmetabolism, multi-organ attack, mitochondria degeneration and ferroptosis. Our suggested elucidated pathological sequence is: a) spike protein subunit S1 docking with sialylated membrane glycoproteins/receptors (ACE2, CD147), and S2 subunit fusion with the lipid layer; b) cell membrane morpho-functional changes due to the consequent electro-chemical variations and viroporin action, which induce an altered ion channel function and intracellular cation accumulation; c) additional intracellular iron concentration due to a deregulated hepcidin-ferroportin axis, with higher hepcidin levels. Viral invasion may also affect erythrocytes/erythroid precursors, endothelial cells and macrophages, through SA and CD147 receptors, with relative hemoglobin and iron/calcium dysmetabolism. AB0 blood group, hemochromatosis, or environmental elements may represent possible factors which affect individual susceptibility to COVID-19. Conclusions: our literature analysis confirms the combined role of SA molecules, ACE2, CD147, viroporins and hepcidin in determining the cation dysmetabolism and final ferroptosis in the cells infected by SARS-CoV-2. The altered ion channels and electrochemical gradients of the cell membrane have a pivotal role in the virus entry and cell dysmetabolism, with subsequent multi-organ immune-inflammatory degeneration and erythrocyte/hemoglobin alterations.
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Affiliation(s)
- Attilio Cavezzi
- Eurocenter Venalinfa, San Benedetto del Tronto, AP, 63074, Italy
| | | | - Emidio Troiani
- Cardiology Unit, Social Security Institute, State Hospital, Cailungo, 47893, San Marino
| | - Salvatore Corrao
- Department of Clinical Medicine, Internal Medicine Division,, ARNAS Civico Di Cristina Benfratelli Hospital Trust, Palermo, Italy
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16
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Cavezzi A, Menicagli R, Troiani E, Corrao S. COVID-19, Cation Dysmetabolism, Sialic Acid, CD147, ACE2, Viroporins, Hepcidin and Ferroptosis: A Possible Unifying Hypothesis. F1000Res 2022; 11:102. [PMID: 35340277 PMCID: PMC8921693 DOI: 10.12688/f1000research.108667.2] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/17/2022] [Indexed: 12/15/2022] Open
Abstract
Background: iron and calcium dysmetabolism, with hyperferritinemia, hypoferremia, hypocalcemia and anemia have been documented in the majority of COVID-19 patients at later/worse stages. Furthermore, complementary to ACE2, both sialic acid (SA) molecules and CD147 proved relevant host receptors for SARS-CoV-2 entry, which explains the viral attack to multiple types of cells, including erythrocytes, endothelium and neural tissue. Several authors advocated that cell ferroptosis may be the core and final cell degenerative mechanism. Methods: a literature research was performed in several scientific search engines, such as PubMed Central, Cochrane Library, Chemical Abstract Service. More than 500 articles were retrieved until mid-December 2021, to highlight the available evidence about the investigated issues. Results: based on COVID-19 literature data, we have highlighted a few pathophysiological mechanisms, associated with virus-based cation dysmetabolism, multi-organ attack, mitochondria degeneration and ferroptosis. Our suggested elucidated pathological sequence is: a) spike protein subunit S1 docking with sialylated membrane glycoproteins/receptors (ACE2, CD147), and S2 subunit fusion with the lipid layer; b) cell membrane morpho-functional changes due to the consequent electro-chemical variations and viroporin action, which induce an altered ion channel function and intracellular cation accumulation; c) additional intracellular iron concentration due to a deregulated hepcidin-ferroportin axis, with higher hepcidin levels. Viral invasion may also affect erythrocytes/erythroid precursors, endothelial cells and macrophages, through SA and CD147 receptors, with relative hemoglobin and iron/calcium dysmetabolism. AB0 blood group, hemochromatosis, or environmental elements may represent possible factors which affect individual susceptibility to COVID-19. Conclusions: our literature analysis confirms the combined role of SA molecules, ACE2, CD147, viroporins and hepcidin in determining the cation dysmetabolism and final ferroptosis in the cells infected by SARS-CoV-2. The altered ion channels and electrochemical gradients of the cell membrane have a pivotal role in the virus entry and cell dysmetabolism, with subsequent multi-organ immune-inflammatory degeneration and erythrocyte/hemoglobin alterations.
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Affiliation(s)
- Attilio Cavezzi
- Eurocenter Venalinfa, San Benedetto del Tronto, AP, 63074, Italy
| | | | - Emidio Troiani
- Cardiology Unit, Social Security Institute, State Hospital, Cailungo, 47893, San Marino
| | - Salvatore Corrao
- Department of Clinical Medicine, Internal Medicine Division,, ARNAS Civico Di Cristina Benfratelli Hospital Trust, Palermo, Italy
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17
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Padeniya P, Goonasekara H, Abeysekera G, Jayasekara R, Dissanayake V. Frequency of Hereditary Hemochromatosis Gene (HFE) Variants in Sri Lankan Transfusion-Dependent Beta-Thalassemia Patients and Their Association With the Serum Ferritin Level. Front Pediatr 2022; 10:890989. [PMID: 35903164 PMCID: PMC9315227 DOI: 10.3389/fped.2022.890989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 06/14/2022] [Indexed: 11/13/2022] Open
Abstract
INTRODUCTION Co-inheritance of hereditary hemochromatosis (HFE) gene variants p. C282Y and p.H63D worsen iron overload in transfusion-dependent thalassemia. Data on the HFE gene variants in Sri Lankan patients with thalassemia have not been extensively studied. This study aimed to analyze the p.C282Y and p.H63D variants in transfusion-dependent beta (β) and HbE/β-thalassemia patients and establish an association between these variants and their serum ferritin levels. MATERIALS AND METHODS A total of 125 transfusion-dependent β-thalassemia major and HbE/β thalassemia patients were tested for the c.845G>A (p.C282Y) and c.187C>G (p.H63D) HFE gene variants using the multiplex Amplification Refractory Mutation System Polymerase Chain Reaction method. For phenotype-genotype correlation, serum ferritin levels, the erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels were measured. The standard descriptive statistics were used for data analysis. RESULTS The study cohort consisted of transfusion-dependent 123 β-thalassemia and 2 HbE/β-thalassemia patients. The p.C282Y variant was not detected in any patient; allele frequency for the wild type (c.845GG) was 100%. Twenty-three patients were heterozygous for the p.H63D variant allele, and the allele frequencies were c.187CC 91.8%, c.187CG 9.2%, and c.187GG 0%. The mean serum ferritin level was relatively higher (mean level 4,987 ng/ml) in the p.H63D heterozygous (c.187CG) group compared to the wild type (c.187CC) group (mean level 4,571 ng/ml), but the difference was statistically not significant (p = 0.865). Among the total study population, CRP, ESR, and serum glutamine aspartate transaminase (SGPT) were elevated in 9 (7.2%), 65 (52%), and 82 (65.6%) patients, respectively. Among the p.H63D c.187CG group, elevated CRP, ESR, and SGPT were present in 5 (5%), 15 (12%), and 18 (14.4%) patients, respectively. The detected sample number was low to correlate with the confounding effect of inflammatory disorders and liver damage on the serum ferritin levels. CONCLUSIONS The HFE gene variant p.C282Y is unlikely to cause iron overload in the Asian β-thalassemia patients; the rarity of this variant in the study cohort replicates the findings of other South Asian population studies of this variant. The presence of the p.H63D variant could be a potential risk factor for iron overload in the β-thalassemia patients. A more extensive cohort study is required to validate this finding.
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Affiliation(s)
- Padmapani Padeniya
- Department of Anatomy, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka
| | - Hemali Goonasekara
- Department of Anatomy, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
| | - Gayan Abeysekera
- Department of Anatomy, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
| | - Rohan Jayasekara
- Department of Anatomy, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
| | - Vajira Dissanayake
- Department of Anatomy, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
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18
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Han P, Liu T, Vaquette C, Frazer D, Anderson G, Ivanovski S. Iron accumulation is associated with periodontal destruction in a mouse model of HFE-related haemochromatosis. J Periodontal Res 2021; 57:294-304. [PMID: 34855211 DOI: 10.1111/jre.12959] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 11/03/2021] [Accepted: 11/17/2021] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To investigate the effect of Hfe gene mutation on the distribution of iron and periodontal bone loss in periodontal tissues. BACKGROUND DATA It remains unclear how tissue iron loading affects the periodontium architectures in a genetic animal model of hereditary haemochromatosis (HH). METHODS Male C57BL/6 Hfe-/- (8 weeks old) and wild-type (WT) mice were utilized to examine the iron distribution in periodontal tissues, as well as periodontal tissues changes using micro-computed tomography and histomorphometric analysis. Furthermore, tissue inflammatory mediators, bone markers and periodontal pathogens were carried out in PFA-fixed paraffin-embedded tissues using ELISA, RT-qPCR and genomic DNA qPCR, respectively. RESULTS Excessive iron deposition was found in the periodontal ligament, gingiva and alveolar bone in Hfe-/- mice relative to their WT counterparts. This, in turn, was associated with significant periodontal bone loss, increased cemento-enamel junction-alveolar bone crest distance and decreased expression of molecules involved in bone development and turnover. Furthermore, the pro-inflammatory cytokine - interleukin 6 and periodontal bacteria - Campylobacter rectus were significantly increased in Hfe-/- mice compared with WT controls. CONCLUSION Our results suggest that the iron loading in a mouse model of HH decreases alveolar bone formation and leads to alterations in the inflammatory state in the periodontium. Periodontal health should be assessed during the clinical assessment of HFE-HH patients.
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Affiliation(s)
- Pingping Han
- School of Dentistry, Centre for Orofacial Regeneration, Reconstruction and Rehabilitation (COR3), Epigenetics Nanodiagnostics and therapeutics Group, The University of Queensland, Herston, QLD, Australia.,School of Dentistry, The University of Queensland, Herston, QLD, Australia
| | - Tianqing Liu
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Cedryck Vaquette
- School of Dentistry, The University of Queensland, Herston, QLD, Australia
| | - David Frazer
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Gregory Anderson
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia
| | - Sašo Ivanovski
- School of Dentistry, Centre for Orofacial Regeneration, Reconstruction and Rehabilitation (COR3), Epigenetics Nanodiagnostics and therapeutics Group, The University of Queensland, Herston, QLD, Australia.,School of Dentistry, The University of Queensland, Herston, QLD, Australia
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19
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Sandnes M, Vorland M, Ulvik RJ, Reikvam H. HFE Genotype, Ferritin Levels and Transferrin Saturation in Patients with Suspected Hereditary Hemochromatosis. Genes (Basel) 2021; 12:genes12081162. [PMID: 34440336 PMCID: PMC8394043 DOI: 10.3390/genes12081162] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/26/2021] [Accepted: 07/28/2021] [Indexed: 01/04/2023] Open
Abstract
HFE hemochromatosis is characterized by increased iron absorption and iron overload due to variants of the iron-regulating HFE gene. Overt disease is mainly associated with homozygosity for the C282Y variant, although the H63D variant in compound heterozygosity with C282Y (C282Y/H63D) contributes to disease manifestation. In this observational study, we describe the association between biochemical findings, age, gender and HFE genotype in patients referred from general practice to a tertiary care referral center for diagnostic workup based on suspected hemochromatosis due to persistent hyperferritinemia and HFE variants. C282Y and H63D homozygosity were, respectively, the most and least prevalent genotypes and we found a considerable variation in transferrin saturation and ferritin levels independent of HFE genotype, which may indeed represent a diagnostic challenge in general practice. While our results confirm C282Y homozygosity as the major cause of iron accumulation, non-C282Y homozygotes also displayed mild to moderate hyperferritinemia with median ferritin levels at 500-700 µg/L, well above the reference cut-off. Such findings have traditionally been ignored in the clinic, and initiation of iron depletion has largely been restricted to C282Y homozygotes. Nevertheless, superfluous iron can aggravate pathogenesis in combination with other diseases and risk factors, such as inflammation, cancer and hepatopathy, and this possibility should not be neglected by clinicians.
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Affiliation(s)
- Miriam Sandnes
- Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway; (M.S.); (R.J.U.)
| | - Marta Vorland
- Department of Cancer Genomics, Haukeland University Hospital, N-5021 Bergen, Norway;
| | - Rune J. Ulvik
- Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway; (M.S.); (R.J.U.)
| | - Håkon Reikvam
- Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway; (M.S.); (R.J.U.)
- Department of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway
- Correspondence: ; Tel.: +47-55-97-50-00
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20
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Con D, Nicoll AJ. Hyperferritinaemia and iron overload in Asian patients: lessons from an Australian tertiary centre experience. Intern Med J 2021; 51:802-805. [PMID: 34047022 DOI: 10.1111/imj.15316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 04/14/2020] [Accepted: 04/15/2020] [Indexed: 11/28/2022]
Abstract
Iron overload is described in Asian patients but presents with a different phenotype and genotype compared to Caucasian patients. We retrospectively identified 64 Asian patients and compared them to 64 matched non-Asian patients with at least one episode of serum ferritin >500 μg/L. Of the Asian patients, one (1.6%) had proven iron overload, while other common causes of hyperferritinaemia included recent blood transfusion (47%), acute infection (11%) and haematological malignancy (8%). A greater proportion of non-Asian patients had hyperferritinaemia secondary to high alcohol intake. Iron overload is rare in Asians and unexplained hyperferritinaemia in Asian patients is more likely to be due to other factors.
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Affiliation(s)
- Danny Con
- Department of Gastroenterology, Eastern Health, Melbourne, Victoria, Australia
| | - Amanda J Nicoll
- Department of Gastroenterology, Eastern Health, Melbourne, Victoria, Australia.,Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia
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21
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Serhan M, Jackemeyer D, Abi Karam K, Chakravadhanula K, Sprowls M, Cay-Durgun P, Forzani E. A novel vertical flow assay for point of care measurement of iron from whole blood. Analyst 2021; 146:1633-1641. [PMID: 33595556 DOI: 10.1039/d0an02351e] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Disorders in iron metabolism are endemic globally, affecting more than several hundred million individuals and often resulting in increased rates of mortality or general deterioration of quality of life. To both prevent and monitor treatment of iron related disorders, we present a point of care medical device which leverages a simple smartphone camera to measure total iron concentration from a finger-prick sample. The system consists of a smartphone and an in-house developed app, a 3D printed sensing chamber and a vertical flow membrane-based sensor strip designed to accommodate 50 μl of whole blood, filter out the cellular components and carry out a colorimetric chelation reaction producing a colour change which is detected by our smartphone device. The app's accuracy and precision were assessed via comparison of the mobile app's RGB output to a reference imaging software, ImageJ for the same colorimetric sensing strip. Correlation plots resulted in slopes of 0.99 and coefficient of determination (R2 = 0.99). The device was determined to have a signal to noise ratio >40 and a mean bias of 2% which both indicate high analytical accuracy and precision (in terms of RGB measurement). The smartphone device's iron concentration readout was then studied using an extensively validated laboratory developed test (LDT) for iron detection, which is an optimized spectrophotometry-based technique (this is considered the gold standard for iron quantification among LDTs). In comparison of the smartphone-based technique with the gold standard LDT, a calibration slope of 0.0004 au μg-1 dL-1, a correlation plot with slope of 1.09 and coefficient of determination (R2) of 0.96 and a mean bias of 5.3%, our device can accurately measure iron levels in blood. With detection times of five minutes, fingerpick sample and sensor cost less than 10 cents, the device shows great promise in being developed as the first ever commercial device for iron quantification in blood.
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Affiliation(s)
- Michael Serhan
- Center for Bioelectronics and Biosensors, Biodesign Institute, Arizona State University, Arizona, USA
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22
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Hereditary hemochromatosis promotes colitis and colon cancer and causes bacterial dysbiosis in mice. Biochem J 2021; 477:3867-3883. [PMID: 32955078 PMCID: PMC7557149 DOI: 10.1042/bcj20200392] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 09/17/2020] [Accepted: 09/21/2020] [Indexed: 12/24/2022]
Abstract
Hereditary hemochromatosis (HH), an iron-overload disease, is a prevalent genetic disorder. As excess iron causes a multitude of metabolic disturbances, we postulated that iron overload in HH disrupts colonic homeostasis and colon–microbiome interaction and exacerbates the development and progression of colonic inflammation and colon cancer. To test this hypothesis, we examined the progression and severity of colitis and colon cancer in a mouse model of HH (Hfe−/−), and evaluated the potential contributing factors. We found that experimentally induced colitis and colon cancer progressed more robustly in Hfe−/− mice than in wild-type mice. The underlying causes were multifactorial. Hfe−/− colons were leakier with lower proliferation capacity of crypt cells, which impaired wound healing and amplified inflammation-driven tissue injury. The host/microflora axis was also disrupted. Sequencing of fecal 16S RNA revealed profound changes in the colonic microbiome in Hfe−/− mice in favor of the pathogenic bacteria belonging to phyla Proteobacteria and TM7. There was an increased number of bacteria adhered onto the mucosal surface of the colonic epithelium in Hfe−/− mice than in wild-type mice. Furthermore, the expression of innate antimicrobial peptides, the first-line of defense against bacteria, was lower in Hfe−/− mouse colon than in wild-type mouse colon; the release of pro-inflammatory cytokines upon inflammatory stimuli was also greater in Hfe−/− mouse colon than in wild-type mouse colon. These data provide evidence that excess iron accumulation in colonic tissue as happens in HH promotes colitis and colon cancer, accompanied with bacterial dysbiosis and loss of function of the intestinal/colonic barrier.
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Jiang X, Hintenlang DE, White RD. Lower limit of iron quantification using dual-energy CT - a phantom study. J Appl Clin Med Phys 2020; 22:299-307. [PMID: 33369002 PMCID: PMC7856509 DOI: 10.1002/acm2.13124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 10/08/2020] [Accepted: 11/20/2020] [Indexed: 11/29/2022] Open
Abstract
Purpose Dual‐energy computed tomography (DECT) has been proposed for quantification of hepatic iron concentration (IC). However, the lower limit of quantification (LLOQ) has not been established, limiting the clinical adoption of this technology. In this study, we aim to (a) establish the LLOQ using phantoms and (b) investigate the effects of patient size, dose level, energy combination, and reconstruction method. Methods Three phantom sizes and eight vials of ferric nitrate solution with IC ranging from 0 to 10 mg/ml were used. DECT scans were performed at 80/140 and 100/140Sn kVp, and using five different levels of CT dose index (CTDI). An image‐domain three‐material‐decomposition algorithm was used to calculate the IC. The LLOQ was determined based on the coefficient of variation from repeated measurements. Results The measured IC correlated strongly with the true IC in the small and medium phantoms (R2 of linear regression > 0.99) and moderately in the large phantom (0.8 < R2<0.9). The LLOQ improved with increased CTDI. At 30 mGy, the LLOQ was found to be 0.50/1.73/6.25 mg/ml in the small/medium/large phantoms, respectively. 80/140Sn kVp resulted in superior LLOQ for all phantom sizes compared to 100/140Sn kVp, primarily due to the difference in their iron enhancement ratios (1.94 and 1.55, respectively). Iterative reconstruction was found to further improve the LLOQ (by ~ 11%), whereas reconstruction kernel smoothness had negligible effect. The LLOQ of iron was significantly higher than that of iodine due to its lack of a useful k‐edge and lower enhancement ratio. Conclusion Iron quantification at clinically important levels was achieved in a small‐ and a medium‐sized phantom using DECT, but proved challenging in a large phantom. Wide spectral separation and accurate calibration were found to be critical to the success of the technology.
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Affiliation(s)
- Xia Jiang
- Department of Radiology, Ohio State University College of Medicine, Columbus, OH, USA
| | - David E Hintenlang
- Department of Radiology, Ohio State University College of Medicine, Columbus, OH, USA
| | - Richard D White
- Department of Radiology, Ohio State University College of Medicine, Columbus, OH, USA
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Jarvik GP, Wang X, Fontanillas P, Kim E, Chanprasert S, Gordon AS, Bastarache L, Kowdley KV, Harrison T, Rosenthal EA, Stanaway IB, Bézieau S, Weinstein SJ, Newcomb PA, Casey G, Platz EA, Visvanathan K, Le Marchand L, Ulrich CM, Hardikar S, Li CI, van Duijnhoven FJ, Gsur A, Campbell PT, Moreno V, Vodička P, Brenner H, Chang-Claude J, Hoffmeister M, Slattery ML, Gunter MJ, Aglago EK, Castellví-Bel S, Kweon SS, Chan AT, Li L, Zheng W, Bishop DT, Giles GG, Rennert G, Offit K, Keku TO, Woods MO, Hampe J, Van Guelpen B, Gallinger SJ, de la Chapelle A, Hampel H, Berndt SI, Tangen CM, Lindblom A, Wolk A, Burnett-Hartman A, Wu AH, White E, Gruber SB, Jenkins MA, Mountain J, Peters U, Crosslin DR. Hemochromatosis risk genotype is not associated with colorectal cancer or age at its diagnosis. HGG ADVANCES 2020; 1:100010. [PMID: 35047832 PMCID: PMC8756515 DOI: 10.1016/j.xhgg.2020.100010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 08/12/2020] [Indexed: 11/28/2022] Open
Abstract
Homozygotes for the higher penetrance hemochromatosis risk allele, HFE c.845G>A (p.Cys282Tyr, or C282Y), have been reported to be at a 2- to 3-fold increased risk for colorectal cancer (CRC). These results have been reported for small sample size studies with no information about age at diagnosis for CRC. An association with age at diagnosis might alter CRC screening recommendations. We analyzed two large European ancestry datasets to assess the association of HFE genotype with CRC risk and age at CRC diagnosis. The first dataset included 59,733 CRC or advanced adenoma cases and 72,351 controls from a CRC epidemiological study consortium. The second dataset included 13,564 self-reported CRC cases and 2,880,218 controls from the personal genetics company, 23andMe. No association of the common hereditary hemochromatosis (HH) risk genotype and CRC was found in either dataset. The odds ratios (ORs) for the association of CRC and HFE C282Y homozygosity were 1.08 (95% confidence interval [CI], 0.91-1.29; p = 0.4) and 1.01 (95% CI, 0.78-1.31, p = 0.9) in the two cohorts, respectively. Age at CRC diagnosis also did not differ by HFE C282Y/C282Y genotype in either dataset. These results indicate no increased CRC risk in individuals with HH genotypes and suggest that persons with HH risk genotypes can follow population screening recommendations for CRC.
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Affiliation(s)
- Gail P. Jarvik
- University of Washington Medical Center, Seattle, WA, USA
| | - Xiaoliang Wang
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | | | | | | | | | | | | | | | | | | | | | | | - Polly A. Newcomb
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- School of Public Health, University of Washington, Seattle, WA
| | - Graham Casey
- University of Virginia, Charlottesville, VA, USA
| | | | - Kala Visvanathan
- Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | | | | | | | | | | | | | | | - Victor Moreno
- Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP) and Department of Clinical Sciences, Faculty of Medicine, University of Barcelona (UB), L’Hospitalet, 08908, Barcelona, Spain
| | - Pavel Vodička
- Institute of Experimental Medicine, Czech Academy of Sciences, Biomedical Center, Medical Faculty Pilsen and 1st Medical Faculty, Charles University, Prague, Czech Republic
| | | | | | | | | | - Marc J. Gunter
- Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Elom K. Aglago
- Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Sergi Castellví-Bel
- Gastroenterology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | - Sun-Seog Kweon
- Chonnam National University Medical School, Gwangju, Korea
| | - Andrew T. Chan
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Li Li
- University of Virginia, Charlottesville, VA, USA
| | - Wei Zheng
- Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | | | - Graham G. Giles
- Cancer Council Victoria, Melbourne, VIC, Australia
- University of Melbourne, Melbourne, VIC, Australia
- Monash University, Melbourne, VIC, Australia
| | - Gad Rennert
- Lady Davis Carmel Medical Center, Haifa, Israel
| | - Kenneth Offit
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | | | - Jochen Hampe
- Technische Universität Dresden (TU Dresden), Dresden, Germany
| | - Bethan Van Guelpen
- Department of Radiation Sciences, Oncology, Umeå University and Wallenberg Centre for Molecular Medicine, Umeå University, Sweden
| | | | | | | | - Sonja I. Berndt
- National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | | | | | - Alicja Wolk
- Karolinska Institutet, Stockholm, Sweden
- Uppsala University, Uppsala, Sweden
| | | | - Anna H. Wu
- University of Southern California, Los Angeles, CA, USA
| | - Emily White
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | | | | | - Mark A. Jenkins
- Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, VIC, Australia
| | | | - Ulrike Peters
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington School of Medicine, Seattle, WA, USA
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Acton RT, Wiener HW, Barton JC. Estimates of European American Ancestry in African Americans Using HFE p.C282Y. Genet Test Mol Biomarkers 2020; 24:578-583. [PMID: 32757954 DOI: 10.1089/gtmb.2020.0154] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background: HFE p.C282Y (chromosome 6p22.2; exon 4, c.845G>A; rs1800562), a hemochromatosis-associated polymorphism in European Americans, is absent in sub-Saharan West African blacks. Methods: We estimated European American ancestry in African Americans (M) using published p.C282Y allele frequencies of sub-Saharan West African blacks; and ≥50 unselected African Americans and ≥50 unselected European Americans in the same city/region. Results: p.C282Y allele frequency in 870 West African blacks (The Gambia, Ghana, Nigeria, Senegal, Sierra Leone) was 0.0000 (confidence interval [95% CI 0.0000-0.0027]). p.C282Y allele frequencies in European Americans were 0.0600 (12,592 participants; five single-site studies) and 0.0673 (54,882 participants; two multisite studies). p.C282Y allele frequencies in African Americans were 0.0102 (3084 participants; five single-site studies) and 0.0122 (30,762 participants; two multisite studies). M for all data was 0.1803 (standard error 0.0049; [95% CI 0.1706-0.1900]). City/region estimates of M differed 1.8-fold: 0.1321, Rochester, NY; 0.1456, Birmingham, AL; 0.1569, Upper Savannah Region, SC; 0.1612, Portland, OR; 0.1746, San Diego, CA; 0.1780, Hartford, CT; 0.1957, District of Columbia; 0.2377, Oakland, CA; and 0.2429, Irvine, CA. Conclusions: Estimates of M using p.C282Y are consistent with those using other autosomal markers, differ across nine cities/regions, and reflect paternal and maternal contributions of European American ancestry in African Americans.
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Affiliation(s)
- Ronald T Acton
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.,Southern Iron Disorders Center, Birmingham, Alabama, USA
| | - Howard W Wiener
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - James C Barton
- Southern Iron Disorders Center, Birmingham, Alabama, USA.,Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
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Wickramasinghe W, Karunathilaka C, Jayasinghe S, Gooneratne L. Transient elevation of serum ferritin in a Sri Lankan with homozygosity for H63D mutation in the HFE gene: a case report. J Med Case Rep 2020; 14:93. [PMID: 32641120 PMCID: PMC7346448 DOI: 10.1186/s13256-020-02428-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 06/01/2020] [Indexed: 11/10/2022] Open
Abstract
INTRODUCTION Hereditary hemochromatosis is an inherited disorder of iron metabolism, characterized by excessive iron deposition in major organs of the body, leading to multi-organ dysfunction. It is a genetically heterogeneous disease caused by mutations in one or more different genes, the most common being mutations in the HFE gene. HFE hereditary hemochromatosis is mostly found in Europeans and is almost always a result of two mutations: C282Y and H63D. The H63D mutation is not as penetrant as the C282Y mutation, but there are rare reported cases of hereditary hemochromatosis with homozygous H63D genotype. While the C282Y mutation is primarily confined to persons of Northern European origin, the H63D mutation is spread worldwide. Other types of hereditary hemochromatosis are rare and broadly defined as non-HFE hereditary hemochromatosis and include mutations in the hemojuvelin gene, hepcidin (HAMP gene), transferrin receptor 2 gene, and ferroportin gene. Hereditary hemochromatosis is commonly found in populations of European origin; in contrast, it is rare and less well understood in Asia. It can be masked by the presence of concurrent iron deficiency or secondary iron overload in thalassemias. CASE PRESENTATION We report the case of a 42-year-old Sri Lankan man investigated for fatigue during a brief upper respiratory tract infection and found to have high liver transaminases and high serum ferritin, which persisted even after complete resolution of the infection. Homozygosity for H63D mutation in the HFE gene was detected. Liver enzymes, serum ferritin, and transferrin saturation normalized following venesections. CONCLUSION This case adds to the literature on the importance of being vigilant and investigating patients suspected for iron overload, including genetic studies for hereditary hemochromatosis, even though it is a rare clinical entity in Asians.
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Affiliation(s)
| | | | - Saroj Jayasinghe
- Department of Pathology, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
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Iron Deficiency Anemia in Children Residing in High and Low-Income Countries: Risk Factors, Prevention, Diagnosis and Therapy. Mediterr J Hematol Infect Dis 2020; 12:e2020041. [PMID: 32670519 PMCID: PMC7340216 DOI: 10.4084/mjhid.2020.041] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 06/12/2020] [Indexed: 12/22/2022] Open
Abstract
Iron deficiency and iron-deficiency anemia (IDA) affects approximately two billion people worldwide, and most of them reside in low- and middle-income countries. In these nations, additional causes of anemia include parasitic infections like malaria, other nutritional deficiencies, chronic diseases, hemoglobinopathies, and lead poisoning. Maternal anemia in resource-poor nations is associated with low birth weight, increased perinatal mortality, and decreased work productivity. Maintaining a normal iron balance in these settings is challenging, as iron-rich foods with good bioavailability are of animal origin and either expensive and/or available in short supply. Apart from infrequent consumption of meat, inadequate vitamin C intake, and diets rich in inhibitors of iron absorption are additional important risk factors for IDA in low-income countries. In-home iron fortification of complementary foods with micronutrient powders has been shown to effectively reduce the risk of iron deficiency and IDA in infants and young children in developing countries but is associated with unfavorable changes in gut flora and induction of intestinal inflammation that may lead to diarrhea and hospitalization. In developed countries, iron deficiency is the only frequent micronutrient deficiency. In the industrialized world, IDA is more common in infants beyond the sixth month of life, in adolescent females with heavy menstrual bleeding, in women of childbearing age and older people. Other special at-risk populations for IDA in developed countries are regular blood donors, endurance athletes, and vegetarians. Several medicinal ferrous or ferric oral iron products exist, and their use is not associated with harmful effects on the overall incidence of infectious illnesses in sideropenic and/or anemic subjects. However, further research is needed to clarify the risks and benefits of supplemental iron for children exposed to parasitic infections in low-income countries, and for children genetically predisposed to iron overload.
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Serhan M, Jackemeyer D, Long M, Sprowls M, Diez Perez I, Maret W, Chen F, Tao N, Forzani E. Total Iron Measurement in Human Serum With a Novel Smartphone-Based Assay. IEEE JOURNAL OF TRANSLATIONAL ENGINEERING IN HEALTH AND MEDICINE 2020; 8:2800309. [PMID: 32832281 PMCID: PMC7433848 DOI: 10.1109/jtehm.2020.3005308] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 05/07/2020] [Accepted: 06/02/2020] [Indexed: 12/15/2022]
Abstract
Background: Abnormally low or high blood iron levels are common health conditions worldwide and can seriously affect an individual's overall well-being. A low-cost point-of-care technology that measures blood iron markers with a goal of both preventing and treating iron-related disorders represents a significant advancement in medical care delivery systems. Methods: A novel assay equipped with an accurate, storable, and robust dry sensor strip, as well as a smartphone mount and (iPhone) app is used to measure total iron in human serum. The sensor strip has a vertical flow design and is based on an optimized chemical reaction. The reaction strips iron ions from blood-transport proteins, reduces Fe(III) to Fe(II), and chelates Fe(II) with ferene, with the change indicated by a blue color on the strip. The smartphone mount is robust and controls the light source of the color reading App, which is calibrated to obtain output iron concentration results. The real serum samples are then used to assess iron concentrations from the new assay, and validated through intra-laboratory and inter-laboratory experiments. The intra-laboratory validation uses an optimized iron detection assay with multi-well plate spectrophotometry. The inter-laboratory validation method is performed in a commercial testing facility (LabCorp). Results: The novel assay with the dry sensor strip and smartphone mount, and App is seen to be sensitive to iron detection with a dynamic range of 50 - [Formula: see text]/dL, sensitivity of 0.00049 a.u/[Formula: see text]/dL, coefficient of variation (CV) of 10.5%, and an estimated detection limit of [Formula: see text]/dL These analytical specifications are useful for predicting iron deficiency and overloads. The optimized reference method has a sensitivity of 0.00093 a.u/[Formula: see text]/dL and CV of 2.2%. The correlation of serum iron concentrations (N = 20) between the optimized reference method and the novel assay renders a slope of 0.95, and a regression coefficient of 0.98, suggesting that the new assay is accurate. Last, a spectrophotometric study of the iron detection reaction kinetics is seen to reveal the reaction order for iron and chelating agent. Conclusion: The new assay is able to provide accurate results in intra- and inter- laboraty validations, and has promising features of both mobility and low-cost manufacturing suitable for global healthcare settings.
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Affiliation(s)
| | | | | | | | | | | | - Fang Chen
- Arizona State UniversityTempeAZ85287USA
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29
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Ristic B, Sivaprakasam S, Narayanan M, Ganapathy V. Hereditary hemochromatosis disrupts uric acid homeostasis and causes hyperuricemia via altered expression/activity of xanthine oxidase and ABCG2. Biochem J 2020; 477:1499-1513. [PMID: 32239172 PMCID: PMC7200644 DOI: 10.1042/bcj20190873] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 03/30/2020] [Accepted: 04/01/2020] [Indexed: 12/20/2022]
Abstract
Hereditary hemochromatosis (HH) is mostly caused by mutations in the iron-regulatory gene HFE. The disease is associated with iron overload, resulting in liver cirrhosis/cancer, cardiomegaly, kidney dysfunction, diabetes, and arthritis. Fe2+-induced oxidative damage is suspected in the etiology of these symptoms. Here we examined, using Hfe-/- mice, whether disruption of uric acid (UA) homeostasis plays any role in HH-associated arthritis. We detected elevated levels of UA in serum and intestine in Hfe-/- mice compared with controls. Though the expression of xanthine oxidase, which generates UA, was not different in liver and intestine between wild type and Hfe-/- mice, the enzymatic activity was higher in Hfe-/- mice. We then examined various transporters involved in UA absorption/excretion. Glut9 expression did not change; however, there was an increase in Mrp4 and a decrease in Abcg2 in Hfe-/- mice. As ABCG2 mediates intestinal excretion of UA and mutations in ABCG2 cause hyperuricemia, we examined the potential connection between iron and ABCG2. We found p53-responsive elements in hABCG2 promoter and confirmed with chromatin immunoprecipitation that p53 binds to this promoter. p53 protein was reduced in Hfe-/- mouse intestine. p53 is a heme-binding protein and p53-heme complex is subjected to proteasomal degradation. We conclude that iron/heme overload in HH increases xanthine oxidase activity and also promotes p53 degradation resulting in decreased ABCG2 expression. As a result, systemic UA production is increased and intestinal excretion of UA via ABCG2 is decreased, causing serum and tissue accumulation of UA, a potential factor in the etiology of HH-associated arthritis.
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Affiliation(s)
- Bojana Ristic
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A
| | - Sathish Sivaprakasam
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A
| | - Monisha Narayanan
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A
| | - Vadivel Ganapathy
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A
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Barton JC, Wiener HH, Acton RT, Adams PC, Eckfeldt JH, Gordeuk VR, Harris EL, McLaren CE, Harrison H, McLaren GD, Reboussin DM. Prevalence of iron deficiency in 62,685 women of seven race/ethnicity groups: The HEIRS Study. PLoS One 2020; 15:e0232125. [PMID: 32324809 PMCID: PMC7179917 DOI: 10.1371/journal.pone.0232125] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 04/07/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Few cross-sectional studies report iron deficiency (ID) prevalence in women of different race/ethnicity and ages in US or Canada. MATERIALS AND METHODS We evaluated screening observations on women who participated between 2001-2003 in a cross-sectional, primary care-based sample of adults ages ≥25 y whose observations were complete: race/ethnicity; age; transferrin saturation; serum ferritin; and HFE p.C282Y and p.H63D alleles. We defined ID using a stringent criterion: combined transferrin saturation <10% and serum ferritin <33.7 pmol/L (<15 μg/L). We compared ID prevalence in women of different race/ethnicity subgrouped by age and determined associations of p.C282Y and p.H63D to ID overall, and to ID in women ages 25-44 y with or without self-reported pregnancy. RESULTS These 62,685 women included 27,079 whites, 17,272 blacks, 8,566 Hispanics, 7,615 Asians, 449 Pacific Islanders, 441 Native Americans, and 1,263 participants of other race/ethnicity. Proportions of women with ID were higher in Hispanics and blacks than whites and Asians. Prevalence of ID was significantly greater in women ages 25-54 y of all race/ethnicity groups than women ages ≥55 y of corresponding race/ethnicity. In women ages ≥55 y, ID prevalence did not differ significantly across race/ethnicity. p.C282Y and p.H63D prevalence did not differ significantly in women with or without ID, regardless of race/ethnicity, age subgroup, or pregnancy. CONCLUSIONS ID prevalence was greater in Hispanic and black than white and Asian women ages 25-54 y. p.C282Y and p.H63D prevalence did not differ significantly in women with or without ID, regardless of race/ethnicity, age subgroup, or pregnancy.
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Affiliation(s)
- James C. Barton
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA and Southern Iron Disorders Center, Birmingham, AL, United States of America
| | - Howard H. Wiener
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, United States of America
| | - Ronald T. Acton
- USA and Southern Iron Disorders Center, Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States of America
| | - Paul C. Adams
- Department of Medicine, London Health Sciences Centre, London, ONT, Canada
| | - John H. Eckfeldt
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, United States of America
| | - Victor R. Gordeuk
- Division of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States of America
| | - Emily L. Harris
- Division of Cancer Control and Population Sciences, Epidemiology and Genomics Research Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America
| | - Christine E. McLaren
- Department of Epidemiology, University of California, Irvine, CA, United States of America
| | - Helen Harrison
- The Western-Fanshawe Collaborative BScN Program, Fanshawe College, London, ONT, Canada
| | - Gordon D. McLaren
- Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, CA, USA and Department of Veterans Affairs Long Beach Healthcare System, Long Beach, CA, United States of America
| | - David M. Reboussin
- Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, United States of America
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Barton JC, Barton JC, Adams PC. Prevalence and characteristics of anti-HCV positivity and chronic hepatitis C virus infection in HFE p.C282Y homozygotes. Ann Hepatol 2020; 18:354-359. [PMID: 31056361 DOI: 10.1016/j.aohep.2018.11.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 10/30/2018] [Accepted: 11/28/2018] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIM Observations of hepatitis C virus (HCV) infection in adults with hemochromatosis are limited. MATERIALS AND METHODS We determined associations of serum ferritin (SF) with anti-HCV in non-Hispanic white North American adults in a post-screening examination. Cases included p.C282Y homozygotes (regardless of screening transferrin saturation (TS) and SF) and participants (regardless of HFE genotype) with high screening TS/SF. Controls included participants without p.C282Y or p.H63D who had normal screening TS/SF. Participants with elevated alanine aminotransferase underwent anti-HCV testing. We determined prevalence of chronic HCV infection in consecutive Alabama and Ontario referred adults with HFE p.C282Y homozygosity. RESULTS In post-screening participants, anti-HCV prevalence was 0.3% [95% CI: 0.02, 2.2] in 294 p.C282Y homozygotes, 9.5% [7.2, 12.3] in 560 Cases without p.C282Y homozygosity, and 0.7% [0.2, 2.3] in 403 Controls. Anti-HCV was detected in 7.2% of 745 participants with and 0.8% of 512 participants without elevated SF (odds ratio 9.9 [3.6, 27.6]; p<0.0001). Chronic HCV infection prevalence in 961 referred patients was 1.0% (10/961) [95% confidence interval (CI): 0.5, 2.0]. Ten patients with chronic HCV infection had median age 45y (range 29-67) and median SF 1163μg/L (range 303-2001). Five of eight (62.5%) patients had biopsy-proven cirrhosis. CONCLUSIONS Odds ratio of anti-HCV was increased in post-screening participants with elevated SF. Prevalence of anti-HCV in post-screening participants with HFE p.C282Y homozygosity and chronic HCV infection in referred adults with HFE p.C282Y homozygosity in North America is similar to that of Control participants with HFE wt/wt and normal screening TS/SF.
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Affiliation(s)
- James C Barton
- Southern Iron Disorders Center, Birmingham, Birmingham, AL, USA; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
| | | | - Paul C Adams
- Department of Medicine, University of Western Ontario, London, Ontario, Canada
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Piperno A, Pelucchi S, Mariani R. Inherited iron overload disorders. Transl Gastroenterol Hepatol 2020; 5:25. [PMID: 32258529 DOI: 10.21037/tgh.2019.11.15] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 11/12/2019] [Indexed: 12/21/2022] Open
Abstract
Hereditary iron overload includes several disorders characterized by iron accumulation in tissues, organs, or even single cells or subcellular compartments. They are determined by mutations in genes directly involved in hepcidin regulation, cellular iron uptake, management and export, iron transport and storage. Systemic forms are characterized by increased serum ferritin with or without high transferrin saturation, and with or without functional iron deficient anemia. Hemochromatosis includes five different genetic forms all characterized by high transferrin saturation and serum ferritin, but with different penetrance and expression. Mutations in HFE, HFE2, HAMP and TFR2 lead to inadequate or severely reduced hepcidin synthesis that, in turn, induces increased intestinal iron absorption and macrophage iron release leading to tissue iron overload. The severity of hepcidin down-regulation defines the severity of iron overload and clinical complications. Hemochromatosis type 4 is caused by dominant gain-of-function mutations of ferroportin preventing hepcidin-ferroportin binding and leading to hepcidin resistance. Ferroportin disease is due to loss-of-function mutation of SLC40A1 that impairs the iron export efficiency of ferroportin, causes iron retention in reticuloendothelial cell and hyperferritinemia with normal transferrin saturation. Aceruloplasminemia is caused by defective iron release from storage and lead to mild microcytic anemia, low serum iron, and iron retention in several organs including the brain, causing severe neurological manifestations. Atransferrinemia and DMT1 deficiency are characterized by iron deficient erythropoiesis, severe microcytic anemia with high transferrin saturation and parenchymal iron overload due to secondary hepcidin suppression. Diagnosis of the different forms of hereditary iron overload disorders involves a sequential strategy that combines clinical, imaging, biochemical, and genetic data. Management of iron overload relies on two main therapies: blood removal and iron chelators. Specific therapeutic options are indicated in patients with atransferrinemia, DMT1 deficiency and aceruloplasminemia.
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Affiliation(s)
- Alberto Piperno
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,Centre for Rare Diseases, Disorder of Iron Metabolism, ASST-Monza, S. Gerardo Hospital, Monza, Italy
| | - Sara Pelucchi
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Raffaella Mariani
- Centre for Rare Diseases, Disorder of Iron Metabolism, ASST-Monza, S. Gerardo Hospital, Monza, Italy
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Liang YH, Huang KYA, Lee DC, Pang KN, Chen SH. High-precision iron isotope analysis of whole blood, erythrocytes, and serum in adults. J Trace Elem Med Biol 2020; 58:126421. [PMID: 31805477 DOI: 10.1016/j.jtemb.2019.126421] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Revised: 09/13/2019] [Accepted: 10/22/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Iron isotopic composition serves as a biological indicator of Fe metabolism in humans. In the process of Fe metabolism, essential carriers of Fe circulate in the blood and pass through storage organs and intestinal absorptive tissues. This study aimed to establish an analytical method for high-precision Fe isotopic measurement, investigate Fe concentration and isotopic composition in different parts of whole blood, and explore the potential of Fe isotopic composition as an indicator for Fe status within individuals. ANALYTICAL METHODS A total of 23 clinically healthy Taiwanese adults of Han descent were enrolled randomly and Fe isotopic compositions of their whole blood, erythrocytes, and serum were measured. The Fe isotopic analysis was performed by Neptune Plus multiple-collector inductively coupled plasma mass spectrometry with double-spike technique. The precision and reproducibility of the Fe isotopic analysis were monitored by international biological and geological reference materials. MAIN FINDINGS High-precision Fe isotopic measurements were achieved alongside with high consistency in the isotopic data for well-characterized reference materials. The Fe isotopic signatures of whole blood and erythrocytes were resolvable from that of serum, where both whole blood and erythrocytes contained significantly lighter Fe isotopic compositions compared to the case of serum (P = 0.0296 and P = 0.0004, respectively). The δ56/54Fe value of the serum sample was 0.2‰ heavier on an average than those of whole blood or erythrocytes. This isotopic fractionation observed in different parts of whole blood may indicate redox processes involved in Fe cycling, e.g. erythrocyte production and Fe transportation. Moreover, the δ56/54Fe values of whole blood and serum significantly correlated with the hemoglobin level (P = 0.0126 and P = 0.0020, respectively), erythrocyte count (P = 0.0014 and P = 0.0005, respectively), and Mentzer index (P = 0.0055 and P = 0.0011, respectively), suggesting the Fe isotopic composition as an indicator of functional Fe status in healthy adults. The relationships between blood Fe isotopic compositions and relevant biodemographic variables were also examined. While the average Fe concentration of whole blood was significantly higher in males than in females (P = 0.0028), females exhibited a heavier Fe isotopic composition compared to that of males in whole blood (P = 0.0010) and serum (P < 0.0001). A significantly inverse correlation of the whole blood δ56/54Fe value with body mass index of individuals (P = 0.0095) was also observed. CONCLUSION The results presented herein reveal that blood Fe isotopic signature is consequentially linked to baseline erythrocyte parameters in individuals and is significantly affected by the gender and body mass index in the adult population. These findings support the role of Fe isotopic composition as an indicator for the variance of Fe metabolism among adult individuals and populations and warrant further study to elucidate the underlying mechanisms.
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Affiliation(s)
- Yu-Hsuan Liang
- Institute of Earth Sciences, Academia Sinica, Taipei, 11529, Taiwan
| | - Kuan-Ying A Huang
- Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, 33305, Taiwan; School of Medicine, Chang Gung University, Taoyuan, 33302, Taiwan.
| | - Der-Chuen Lee
- Institute of Earth Sciences, Academia Sinica, Taipei, 11529, Taiwan
| | - Kwan-Nang Pang
- Institute of Earth Sciences, Academia Sinica, Taipei, 11529, Taiwan
| | - Shih-Hsiang Chen
- Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, 33305, Taiwan
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Semenova EA, Miyamoto-Mikami E, Akimov EB, Al-Khelaifi F, Murakami H, Zempo H, Kostryukova ES, Kulemin NA, Larin AK, Borisov OV, Miyachi M, Popov DV, Boulygina EA, Takaragawa M, Kumagai H, Naito H, Pushkarev VP, Dyatlov DA, Lekontsev EV, Pushkareva YE, Andryushchenko LB, Elrayess MA, Generozov EV, Fuku N, Ahmetov II. The association of HFE gene H63D polymorphism with endurance athlete status and aerobic capacity: novel findings and a meta-analysis. Eur J Appl Physiol 2020; 120:665-673. [PMID: 31970519 PMCID: PMC7042188 DOI: 10.1007/s00421-020-04306-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 01/16/2020] [Indexed: 12/04/2022]
Abstract
PURPOSE Iron is an important component of the oxygen-binding proteins and may be critical to optimal athletic performance. Previous studies have suggested that the G allele of C/G rare variant (rs1799945), which causes H63D amino acid replacement, in the HFE is associated with elevated iron indexes and may give some advantage in endurance-oriented sports. The aim of the present study was to investigate the association between the HFE H63D polymorphism and elite endurance athlete status in Japanese and Russian populations, aerobic capacity and to perform a meta-analysis using current findings and three previous studies. METHODS The study involved 315 international-level endurance athletes (255 Russian and 60 Japanese) and 809 healthy controls (405 Russian and 404 Japanese). Genotyping was performed using micro-array analysis or by PCR. VO2max in 46 male Russian endurance athletes was determined using gas analysis system. RESULTS The frequency of the iron-increasing CG/GG genotypes was significantly higher in Russian (38.0 vs 24.9%; OR 1.85, P = 0.0003) and Japanese (13.3 vs 5.0%; OR 2.95, P = 0.011) endurance athletes compared to ethnically matched controls. The meta-analysis using five cohorts (two French, Japanese, Spanish, and Russian; 586 athletes and 1416 controls) showed significant prevalence of the CG/GG genotypes in endurance athletes compared to controls (OR 1.96, 95% CI 1.58-2.45; P = 1.7 × 10-9). Furthermore, the HFE G allele was associated with high V̇O2max in male athletes [CC: 61.8 (6.1), CG/GG: 66.3 (7.8) ml/min/kg; P = 0.036]. CONCLUSIONS We have shown that the HFE H63D polymorphism is strongly associated with elite endurance athlete status, regardless ethnicities and aerobic capacity in Russian athletes.
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Affiliation(s)
- Ekaterina A. Semenova
- Department of Molecular Biology and Genetics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
- Department of Biochemistry, Kazan Federal University, Kazan, Russia
| | - Eri Miyamoto-Mikami
- Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan
| | | | - Fatima Al-Khelaifi
- Anti Doping Laboratory Qatar, Sports City, Doha, Qatar
- UCL-Medical School, Royal Free Campus, London, UK
| | - Haruka Murakami
- Department of Physical Activity Research, National Institutes of Biomedical Innovation, Health and Nutrition, NIBIOHN, Tokyo, Japan
| | - Hirofumi Zempo
- Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan
- Faculty of Health and Nutrition, Tokyo Seiei College, Tokyo, Japan
| | - Elena S. Kostryukova
- Department of Molecular Biology and Genetics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
| | - Nikolay A. Kulemin
- Department of Molecular Biology and Genetics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
| | - Andrey K. Larin
- Department of Molecular Biology and Genetics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
| | - Oleg V. Borisov
- Department of Molecular Biology and Genetics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
- Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Bonn, Germany
| | - Motohiko Miyachi
- Department of Physical Activity Research, National Institutes of Biomedical Innovation, Health and Nutrition, NIBIOHN, Tokyo, Japan
| | - Daniil V. Popov
- Laboratory of Exercise Physiology, Institute for Biomedical Problems of the Russian Academy of Sciences, Moscow, Russia
| | | | - Mizuki Takaragawa
- Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan
| | - Hiroshi Kumagai
- Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan
- Research Fellow of Japanese Society for the Promotion of Science, Tokyo, Japan
| | - Hisashi Naito
- Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan
| | - Vladimir P. Pushkarev
- Medical Genetic Centre “Progen”, Moscow, Russia
- Moscow Center of Advanced Sport Technologies, Moscow, Russia
- Department of the Theory of Physical Culture and Biomechanics, Ural State University of Physical Culture, Chelyabinsk, Russia
| | - Dmitry A. Dyatlov
- Department of the Theory of Physical Culture and Biomechanics, Ural State University of Physical Culture, Chelyabinsk, Russia
| | - Eugene V. Lekontsev
- Methodical and Analytical Department, Regional Center for Sports Training, Chelyabinsk, Russia
- Research Institute of Olympic Sports, Ural State University of Physical Culture, Chelyabinsk, Russia
| | - Yuliya E. Pushkareva
- Department of Pediatrics, South Ural State Medical University, Chelyabinsk, Russia
| | | | | | - Edward V. Generozov
- Department of Molecular Biology and Genetics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
| | - Noriyuki Fuku
- Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan
| | - Ildus I. Ahmetov
- Department of Molecular Biology and Genetics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
- Department of Physical Education, Plekhanov Russian University of Economics, Moscow, Russia
- Laboratory of Molecular Genetics, Kazan State Medical University, Kazan, Russia
- Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Byrom St, Liverpool, L3 5AF UK
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Kurniawan AL, Lee YC, Shih CK, Hsieh RH, Chen SH, Chang JS. Alteration in iron efflux affects male sex hormone testosterone biosynthesis in a diet-induced obese rat model. Food Funct 2020; 10:4113-4123. [PMID: 31233037 DOI: 10.1039/c8fo01870g] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
This study was motivated by clinical observations that dysmetabolic iron overload syndrome (DIOS) and an androgen deficiency are common features observed in obese adult men; however, the molecular mechanism underlying the effects of DIOS on androgen deficiency remains to be elucidated. We established a DIOS animal model by feeding Sprague-Dawley rats an iron/fat-enriched diet (50% fat plus 0.25, 1, or 2 g ferric iron per kg diet) for 12 weeks to induce iron dysfunction (indicated by decreased tissue iron efflux) in obese rats. Obese rats fed an iron/fat-enriched diet showed decreased levels of testicular total Testosterone (T) and iron exporter ferroportin but increased levels of testicular iron and hepcidin, and these effects were more evident with a >1 g ferric iron per kg diet. A western blot analysis showed that an iron/fat-enriched diet triggered testicular endoplasmic reticular (ER) stress but decreased mitochondrion biogenesis proteins (PGC1α and TFAM) and T-converting proteins (StAR, CYP11A, and 17β-HSD). TUNEL staining showed that >1 g ferric iron induced apoptosis mainly in germ cells and Leydig's cells. Uncontrolled testicular iron efflux may cause mitochondrial-ER dysfunction and affect T biosynthesis. Future study targeting the testicular hepcidin-ferroportin axis may offer a therapeutic tool to alleviate testicular iron retention and mitochondrial-ER stress in Leydig's cells.
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Affiliation(s)
- Adi Lukas Kurniawan
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei, Taiwan.
| | - Yu-Chieh Lee
- Department of Obstetrics and Gynecology, Taipei Medical University Hospital, Taipei, Taiwan
| | - Chun-Kuang Shih
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei, Taiwan. and School of Food Safety, College of Nutrition, Taipei Medical University, Taipei, Taiwan
| | - Rong-Hong Hsieh
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei, Taiwan.
| | - Seu-Hwa Chen
- Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Jung-Su Chang
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei, Taiwan. and Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei, Taiwan and Nutrition Research Center, Taipei Medical University Hospital, Taipei, Taiwan and Chinese Taipei Society for the Study of Obesity, CTSSO, Taipei, Taiwan
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Abstract
Iron is essential for both the host and its resident microbes, resulting in competition under iron-deficient conditions. However, the molecular details underlying this competition are not fully understood. In this issue, Das et al. (2019) describe how a common gut commensal disrupts the host iron regulatory pathway to prevent uptake when iron is scarce.
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Affiliation(s)
- Sara J Clasen
- Department of Microbiome Science, Max Planck Institute for Developmental Biology, Tübingen 72076, Germany
| | - Ruth E Ley
- Department of Microbiome Science, Max Planck Institute for Developmental Biology, Tübingen 72076, Germany.
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Ferroportin Disease Caused by a Heterozygous Variant p.Cys326Phe in the SLC40A1 Gene and the Efficacy of Therapeutic Phlebotomy in Children. J Pediatr Hematol Oncol 2019; 41:e325-e328. [PMID: 30130274 DOI: 10.1097/mph.0000000000001301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
Therapeutic phlebotomy is recommended for treating hereditary hemochromatosis. However, the procedure and its efficacy for children remain unclear. We describe a young female patient with ferroportin disease, which was confirmed from excess iron deposition within hepatocytes and by identifying a heterozygous variant p.Cys326Phe in SLC40A1. She had been followed without phlebotomy. Liver histology at age 13 years revealed iron deposition progression. Phlebotomy was initiated and her iron markers and imaging findings improved without severe adverse effects. Therapeutic phlebotomy for children is effective and well-tolerated and should be considered as early as possible after a hemochromatosis diagnosis.
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Abstract
BACKGROUND Cluster headache is the most severe primary headache disorder. A genetic basis has long been suggested by family and twin studies; however, little is understood about the genetic variants that contribute to cluster headache susceptibility. METHODS We conducted a literature search of the MEDLINE database using the PubMed search engine to identify all human genetic studies for cluster headache. In this article we provide a review of those genetic studies, along with an overview of the pathophysiology of cluster headache and a brief review of migraine genetics, which have both been significant drivers of cluster headache candidate gene selection. RESULTS The investigation of cluster headache genetic etiology has been dominated by candidate gene studies. Candidate selection has largely been driven by the pathophysiology, such as the striking rhythmic nature of the attacks, which spurred close examination of the circadian rhythm genes CLOCK and HCRTR2. More recently, unbiased genetic approaches such as genome-wide association studies (GWAS) have yielded new genetic avenues of interest including ADCYAP1R1 and MME. CONCLUSIONS The majority of candidate genes studied for cluster headache suffer from poor reproducibility. Broader genetic interrogation through larger unbiased GWAS, exome, and whole genome studies may provide more robust candidates, and in turn provide a clearer understanding of the causes of cluster headache.
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Affiliation(s)
| | | | - Nunu Lund
- 2 Danish Headache Center, Department of Neurology, University of Copenhagen, Denmark
| | - Rigmor Jensen
- 2 Danish Headache Center, Department of Neurology, University of Copenhagen, Denmark
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Allen A, Premawardhena A, Allen S, Rodrigo R, Manamperi A, Perera L, Wray K, Armitage A, Fisher C, Drakesmith A, Robson K, Weatherall D. The p.H63D allele of the HFE gene protects against low iron stores in Sri Lanka. Blood Cells Mol Dis 2019; 76:72-77. [PMID: 30827762 DOI: 10.1016/j.bcmd.2019.02.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 02/19/2019] [Indexed: 01/02/2023]
Abstract
In hereditary hemochromatosis, iron overload is associated with homozygosity for the p.C282Y mutation. A second mutation, p.H63D, occurs at significant frequencies in Europe, North Africa, the Middle East and Asia. Early studies in Sri Lanka indicated that the variant had arisen independently, suggesting that it had been the subject of selective pressure. However, its role in iron absorption is unclear. In a survey of 7526 Sri Lankan secondary school students, we determined hemoglobin genotype and measured red cell indices, serum ferritin, transferrin receptor, iron zinc protoporphyrin and hepcidin. These variables were compared according to the presence or absence of the p.H63D variant in a subset of 1313 students for whom DNA samples were available. Students were classified as having low red cell indices if they had an MCV <80 fl and/or MCH <27 pg. Hetero and/or homozygosity for the p.H63D variant was more common in students with normal than low red cell indices (16.4% and 11.9% respectively; p = 0.019). Iron biomarkers and red cell indices were greater in children with the p.H63D variant than in normal and this was statistically significant for MCV (p = 0.046). Our findings suggest that selective pressure by mild iron deficiency contributes to the high frequencies of the p.H63D variant.
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Affiliation(s)
- Angela Allen
- MRC Molecular Hematology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK; Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK.
| | - Anuja Premawardhena
- Faculty of Medicine, University of Kelaniya, Sri Lanka; Thalassemia Care Unit, North Colombo Teaching Hospital, Ragama, Sri Lanka
| | - Stephen Allen
- Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK
| | - Rexan Rodrigo
- Faculty of Medicine, University of Kelaniya, Sri Lanka; Thalassemia Care Unit, North Colombo Teaching Hospital, Ragama, Sri Lanka
| | | | - Luxman Perera
- Thalassemia Care Unit, North Colombo Teaching Hospital, Ragama, Sri Lanka
| | - Katherine Wray
- MRC Immunology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Andrew Armitage
- MRC Immunology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Christopher Fisher
- MRC Molecular Hematology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Alexander Drakesmith
- MRC Immunology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Kathryn Robson
- MRC Molecular Hematology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - David Weatherall
- MRC Molecular Hematology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
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Wade QW, Chiou B, Connor JR. Iron uptake at the blood-brain barrier is influenced by sex and genotype. PHARMACOLOGY OF RESTLESS LEGS SYNDROME (RLS) 2019; 84:123-145. [DOI: 10.1016/bs.apha.2019.02.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Yang J, Lun Y, Shuai X, Liu T, Wu Y. Late-onset Hemochromatosis: Co-inheritance of β-thalassemia and Hereditary Hemochromatosis in a Chinese Family: A Case Report and Epidemiological Analysis of Diverse Populations. Intern Med 2018; 57:3433-3438. [PMID: 28943547 PMCID: PMC6306545 DOI: 10.2169/internalmedicine.8628-16] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Hereditary hemochromatosis and β-thalassemia can both result in the inappropriately low production of the hormone hepcidin, which leads to an increase in intestinal absorption and excessive iron deposition in the parenchymal cells. To the best of our knowledge, there have been no reports on the coexistence of the two disorders in China. We herein report a case in a Chinese who presented with late-onset hepatic cirrhosis with hereditary hemochromatosis and β-thalassemia. We analyzed the pedigree of the two disorders and the iron status in his family members. Our case supports that a heterozygous H63D mutation can interact with β-thalassemia, leading to late-onset hemochromatosis.
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Affiliation(s)
- Jinjun Yang
- Department of Hematology and Hematology Research Laboratory, West China Hospital, Sichuan University, China
| | - Yan Lun
- Department of Hematology and Hematology Research Laboratory, West China Hospital, Sichuan University, China
| | - Xiao Shuai
- Department of Hematology and Hematology Research Laboratory, West China Hospital, Sichuan University, China
| | - Ting Liu
- Department of Hematology and Hematology Research Laboratory, West China Hospital, Sichuan University, China
| | - Yu Wu
- Department of Hematology and Hematology Research Laboratory, West China Hospital, Sichuan University, China
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Japan
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Simão M, Camacho A, Ostertag A, Cohen-Solal M, Pinto IJ, Porto G, Hang Korng E, Cancela ML. Iron-enriched diet contributes to early onset of osteoporotic phenotype in a mouse model of hereditary hemochromatosis. PLoS One 2018; 13:e0207441. [PMID: 30427936 PMCID: PMC6241130 DOI: 10.1371/journal.pone.0207441] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 10/31/2018] [Indexed: 01/12/2023] Open
Abstract
Osteoporosis is associated with chronic iron overload secondary to hereditary hemochromatosis (HH), but the causative mechanisms are incompletely understood. The main objective of this study was to investigate the role of dietary iron on osteoporosis, using as biological model the Hfe-KO mice, which have a systemic iron overload. We showed that these mice show an increased susceptibility for developing a bone loss phenotype compared to WT mice, which can be exacerbated by an iron rich diet. The dietary iron overload caused an increase in inflammation and iron incorporation within the trabecular bone in both WT and Hfe-KO mice. However, the osteoporotic phenotype was only evident in Hfe-KO mice fed the iron-enriched diet. This appeared to result from an imbalance between bone formation and bone resorption driven by iron toxicity associated to Hfe-KO and confirmed by a decrease in bone microarchitecture parameters (identified by micro-CT) and osteoblast number. These findings were supported by the observed downregulation of bone metabolism markers and upregulation of ferritin heavy polypeptide 1 (Fth1) and transferrin receptor-1 (Tfrc), which are associated with iron toxicity and bone loss phenotype. In WT mice the iron rich diet was not enough to promote a bone loss phenotype, essentially due to the concomitant depression of bone resorption observed in those animals. In conclusion the dietary challenge influences the development of osteoporosis in the HH mice model thus suggesting that the iron content in the diet may influence the osteoporotic phenotype in systemic iron overload conditions.
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Affiliation(s)
- Márcio Simão
- PhD Program in Biomedical Sciences, Department of Biomedical Sciences and Medicine (DCBM), University of Algarve, Faro, Portugal
- Centre of Marine Sciences (CCMAR), University of Algarve, Faro, Portugal
| | - António Camacho
- Department of Orthopedics, Hospital de Cascais, Alcabideche, Portugal
| | - Agnès Ostertag
- Inserm U1132, Bioscar, Hôpital Lariboisiére, pôle locomoteur, service de rhumatologie, Université Paris 7 Denis Diderot, Paris, France
| | - Martine Cohen-Solal
- Inserm U1132, Bioscar, Hôpital Lariboisiére, pôle locomoteur, service de rhumatologie, Université Paris 7 Denis Diderot, Paris, France
| | - I. Jorge Pinto
- Basic and Clinical Research on Iron Biology, Institute for Molecular and Cell Biology (IBMC) and I3S –Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal
| | - Graça Porto
- Basic and Clinical Research on Iron Biology, Institute for Molecular and Cell Biology (IBMC) and I3S –Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal
- Pathology and Molecular Immunology Department, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
- Hematology Service, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal
| | - Ea Hang Korng
- Inserm U1132, Bioscar, Hôpital Lariboisiére, pôle locomoteur, service de rhumatologie, Université Paris 7 Denis Diderot, Paris, France
| | - M. Leonor Cancela
- Centre of Marine Sciences (CCMAR), University of Algarve, Faro, Portugal
- Pathology and Molecular Immunology Department, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
- Department of Biomedical Sciences and Medicine (DCBM), University of Algarve, Faro, Portugal
- Algarve Biomedical Center, University of Algarve, Campus de Gambelas, Faro, Portugal
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43
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Burlet B, Bourgeois V, Buriller C, Aral B, Airaud F, Garrec C, Bézieau S, Gardie B, Girodon F. High HFE mutation incidence in idiopathic erythrocytosis. Br J Haematol 2018; 185:794-795. [PMID: 30407617 DOI: 10.1111/bjh.15631] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- Bénédicte Burlet
- Service d'Hématologie Biologique, Pôle Biologie, CHU de Dijon, Dijon, France
| | - Valentin Bourgeois
- Service d'Hématologie Biologique, Pôle Biologie, CHU de Dijon, Dijon, France
| | - Céline Buriller
- Laboratoire de génétique chromosomique et moléculaire, Pôle Biologie, CHU de Dijon, Dijon, France
| | - Bernard Aral
- Laboratoire de génétique chromosomique et moléculaire, Pôle Biologie, CHU de Dijon, Dijon, France
| | - Fabrice Airaud
- Service de Génétique Médicale, CHU de Nantes, Nantes, France
| | - Céline Garrec
- Service de Génétique Médicale, CHU de Nantes, Nantes, France
| | - Stéphane Bézieau
- Service de Génétique Médicale, CHU de Nantes, Nantes, France.,L'institut du Thorax, INSERM, CNRS, UNIV Nantes, Nantes, France
| | - Betty Gardie
- L'institut du Thorax, INSERM, CNRS, UNIV Nantes, Nantes, France.,Ecole Pratique des Hautes, EPHE, PSL research University, France.,Laboratory of Excellence GR-Ex, Paris
| | - François Girodon
- Service d'Hématologie Biologique, Pôle Biologie, CHU de Dijon, Dijon, France.,Laboratory of Excellence GR-Ex, Paris.,Inserm U1231, Université de Bourgogne, Dijon, France
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44
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Boyer E, Le Gall-David S, Martin B, Fong SB, Loréal O, Deugnier Y, Bonnaure-Mallet M, Meuric V. Increased transferrin saturation is associated with subgingival microbiota dysbiosis and severe periodontitis in genetic haemochromatosis. Sci Rep 2018; 8:15532. [PMID: 30341355 PMCID: PMC6195524 DOI: 10.1038/s41598-018-33813-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 09/25/2018] [Indexed: 02/08/2023] Open
Abstract
Genetic haemochromatosis (GH) is responsible for iron overload. Increased transferrin saturation (TSAT) has been associated with severe periodontitis, which is a chronic inflammatory disease affecting tissues surrounding the teeth and is related to dysbiosis of the subgingival microbiota. Because iron is essential for bacterial pathogens, alterations in iron homeostasis can drive dysbiosis. To unravel the relationships between serum iron biomarkers and the subgingival microbiota, we analysed samples from 66 GH patients. The co-occurrence analysis of the microbiota showed very different patterns according to TSAT. Healthy and periopathogenic bacterial clusters were found to compete in patients with normal TSAT (≤45%). However, significant correlations were found between TSAT and the proportions of Porphyromonas and Treponema, which are two genera that contain well-known periopathogenic species. In patients with high TSAT, the bacterial clusters exhibited no mutual exclusion. Increased iron bioavailability worsened periodontitis and promoted periopathogenic bacteria, such as Treponema. The radical changes in host-bacteria relationships and bacterial co-occurrence patterns according to the TSAT level also suggested a shift in the bacterial iron supply from transferrin to NTBI when TSAT exceeded 45%. Taken together, these results indicate that iron bioavailability in biological fluids is part of the equilibrium between the host and its microbiota.
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Affiliation(s)
- Emile Boyer
- Univ Rennes, INSERM, INRA, CHU Rennes, Institut NuMeCan (Nutrition, Metabolism and Cancer), Rennes, F-35000, France.
- CHU de Rennes, Service d'Odontologie, Rennes, 35033, France.
| | - Sandrine Le Gall-David
- Univ Rennes, INSERM, INRA, CHU Rennes, Institut NuMeCan (Nutrition, Metabolism and Cancer), Rennes, F-35000, France
| | - Bénédicte Martin
- Univ Rennes, INSERM, INRA, CHU Rennes, Institut NuMeCan (Nutrition, Metabolism and Cancer), Rennes, F-35000, France
| | - Shao Bing Fong
- Univ Rennes, INSERM, INRA, CHU Rennes, Institut NuMeCan (Nutrition, Metabolism and Cancer), Rennes, F-35000, France
| | - Olivier Loréal
- Univ Rennes, INSERM, INRA, CHU Rennes, Institut NuMeCan (Nutrition, Metabolism and Cancer), Rennes, F-35000, France
| | - Yves Deugnier
- CHU de Rennes, Service des Maladies du Foie, Rennes, 35033, France
- CIC 1414, Inserm, Rennes, 35033, France
| | - Martine Bonnaure-Mallet
- Univ Rennes, INSERM, INRA, CHU Rennes, Institut NuMeCan (Nutrition, Metabolism and Cancer), Rennes, F-35000, France
- CHU de Rennes, Service d'Odontologie, Rennes, 35033, France
| | - Vincent Meuric
- Univ Rennes, INSERM, INRA, CHU Rennes, Institut NuMeCan (Nutrition, Metabolism and Cancer), Rennes, F-35000, France
- CHU de Rennes, Service d'Odontologie, Rennes, 35033, France
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45
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Ciesielski TH, Schwartz J, Bellinger DC, Hauser R, Amarasiriwardena C, Sparrow D, Wright RO. Iron-processing genotypes, nutrient intakes, and cadmium levels in the Normative Aging Study: Evidence of sensitive subpopulations in cadmium risk assessment. ENVIRONMENT INTERNATIONAL 2018; 119:527-535. [PMID: 30059941 DOI: 10.1016/j.envint.2018.06.040] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 06/07/2018] [Accepted: 06/30/2018] [Indexed: 06/08/2023]
Abstract
BACKGROUND Because iron and cadmium share common transport mechanisms, iron-processing protein variants such as HFE C282Y, HFE H63D, and Transferrin P570S may influence cadmium metabolism. Our aim was to evaluate associations between common HFE and Transferrin polymorphisms and toenail cadmium levels among older men. METHODS In a longitudinal cohort of men age 51-97, the Normative Aging Study (NAS), we evaluated toenail cadmium concentrations and missense single nucleotide polymorphisms (SNPs) in the HFE and Transferrin genes. We fit age-adjusted models to estimate associations between genotypes and toenail cadmium concentrations. We then considered potential interactions with smoking status, hemoglobin, and nutritional intakes known to modulate cadmium absorption. For the significant interactions, we also evaluated genotype specific effect estimates. RESULTS HFE and Transferrin genotypes were not associated with toenail cadmium concentrations in the main effect analyses, but there were significant interactions between HFE H63D and hemoglobin (pinteraction = 0.021), as well as HFE H63D and vitamin C intake (pinteraction = 0.048). Genotype specific effect estimates suggested: 1) an inverse relationship between hemoglobin and cadmium levels among HFE H63D homozygotes, and 2) an inverse relationship between vitamin C intake and cadmium levels that strengthens with the number of HFE H63D variant alleles a subject carries. CONCLUSIONS These findings suggest that sensitive subpopulations defined by diet, hemoglobin level, and genotype may absorb more cadmium from their environment and thus should be considered in cadmium risk analyses. These findings are particularly relevant given the high prevalence of the H63D variant worldwide.
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Affiliation(s)
| | - Joel Schwartz
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
| | - David C Bellinger
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Neurology, Children's Hospital Boston, Boston, MA, USA.
| | - Russ Hauser
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
| | - Chitra Amarasiriwardena
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - David Sparrow
- VA Normative Aging Study, Veterans Affairs Boston Healthcare System and the Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
| | - Robert O Wright
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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46
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Rozwadowska K, Daniłowicz-Szymanowicz L, Fijałkowski M, Sikorska K, Gałąska R, Kozłowski D, Gruchała M, Raczak G. Can two-dimensional speckle tracking echocardiography be useful for left ventricular assessment in the early stages of hereditary haemochromatosis? Echocardiography 2018; 35:1772-1781. [DOI: 10.1111/echo.14141] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 08/16/2018] [Accepted: 08/25/2018] [Indexed: 12/23/2022] Open
Affiliation(s)
| | | | | | - Katarzyna Sikorska
- Department of Tropical Medicine and Epidemiology; Medical University of Gdansk; Gdansk Poland
| | - Rafał Gałąska
- I Department of Cardiology; Medical University of Gdansk; Gdansk Poland
| | - Dariusz Kozłowski
- II Department of Cardiology and Electrotherapy; Medical University of Gdansk; Gdansk Poland
| | - Marcin Gruchała
- I Department of Cardiology; Medical University of Gdansk; Gdansk Poland
| | - Grzegorz Raczak
- II Department of Cardiology and Electrotherapy; Medical University of Gdansk; Gdansk Poland
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47
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De Falco L, Tortora R, Imperatore N, Bruno M, Capasso M, Girelli D, Castagna A, Caporaso N, Iolascon A, Rispo A. The role of TMPRSS6 and HFE variants in iron deficiency anemia in celiac disease. Am J Hematol 2018; 93:383-393. [PMID: 29194702 DOI: 10.1002/ajh.24991] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 11/23/2017] [Accepted: 11/27/2017] [Indexed: 12/14/2022]
Abstract
We investigated the role of HFE C282Y, H63D, and TMPRSS6 A736V variants in the pathogenesis of iron deficiency anemia (IDA) in celiac disease (CD) patients, at diagnosis and after 1 year of gluten-free diet (GFD). Demographic and clinical features were prospectively recorded for all CD patients between 2013 and 2017. C282Y, H63D, and A736V variants were evaluated for CD patients and controls. Finally, 505 consecutive CD patients and 539 age-matched control subjects were enrolled. At diagnosis, 229 CD subjects had IDA (45.3%), with a subgroup of anemic patients (45.4%) presented persistent IDA at follow-up. C282Y allele frequency was significantly increased in CD compared with controls (1.1% vs 0.2%, P = .001), whereas H63D and A736V allele frequencies were similar among patients and controls (P = .92 and .84, respectively). At diagnosis, C282Y variant in anemic CD patients was significantly increased compared to nonanemic group (2% and 0.5%, P = .04). At follow-up, A736V was significantly increased in IDA persistent than in IDA not persistent (57.7% vs 35.2%, P < .0001). CD patients with H63D mutation showed higher Hb, MCV, serum iron, and ferritin levels than subjects without HFE mutations. Decreased hepcidin values were observed in anemic compared to nonanemic subjects at follow-up (1.22 ± 1.14 vs 2.08 ± 2.15, P < .001). This study suggests a protective role of HFE in IDA CD patients and confirms the role of TMPRSS6 in predicting oral iron response modulating hepcidin action on iron absorption. Iron supplementation therapeutic management in CD could depend on TMPRSS6 genotype that could predict persistent IDA despite iron supplementation and GFD.
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Affiliation(s)
- Luigia De Falco
- Department of Molecular Medicine and Medical Biotechnologies; University “Federico II” of Naples; Naples Italy
- CEINGE, Advanced Biotechnologies; Naples Italy
| | - Raffaella Tortora
- Gastroenterology, Department of Clinical Medicine and Surgery; School of Medicine “Federico II” of Naples; Naples Italy
| | - Nicola Imperatore
- Gastroenterology, Department of Clinical Medicine and Surgery; School of Medicine “Federico II” of Naples; Naples Italy
| | - Mariasole Bruno
- CEINGE, Advanced Biotechnologies; Naples Italy
- Department of Medicine, Section of Internal Medicine; University of Verona; Verona Italy
| | - Mario Capasso
- Department of Molecular Medicine and Medical Biotechnologies; University “Federico II” of Naples; Naples Italy
- CEINGE, Advanced Biotechnologies; Naples Italy
- SDN Diagnostic and Nuclear Research Institute; Naples Italy
| | - Domenico Girelli
- Department of Medicine, Section of Internal Medicine; University of Verona; Verona Italy
| | - Annalisa Castagna
- Department of Medicine, Section of Internal Medicine; University of Verona; Verona Italy
| | - Nicola Caporaso
- Gastroenterology, Department of Clinical Medicine and Surgery; School of Medicine “Federico II” of Naples; Naples Italy
| | - Achille Iolascon
- Department of Molecular Medicine and Medical Biotechnologies; University “Federico II” of Naples; Naples Italy
- CEINGE, Advanced Biotechnologies; Naples Italy
| | - Antonio Rispo
- Gastroenterology, Department of Clinical Medicine and Surgery; School of Medicine “Federico II” of Naples; Naples Italy
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48
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Duck KA, Neely EB, Simpson IA, Connor JR. A role for sex and a common HFE gene variant in brain iron uptake. J Cereb Blood Flow Metab 2018; 38:540-548. [PMID: 28350201 PMCID: PMC5851144 DOI: 10.1177/0271678x17701949] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 02/23/2017] [Accepted: 03/07/2017] [Indexed: 11/16/2022]
Abstract
HFE (high iron) is an essential protein for regulating iron transport into cells. Mutations of the HFE gene result in loss of this regulation causing accumulation of iron within the cell. The mutated protein has been found increasingly in numerous neurodegenerative disorders in which increased levels of iron in the brain are reported. Additionally, evidence that these mutations are associated with elevated brain iron challenges the paradigm that the brain is protected by the blood-brain barrier. While much has been studied regarding the role of HFE in cellular iron uptake, it has remained unclear what role the protein plays in the transport of iron into the brain. We investigated regulation of iron transport into the brain using a mouse model with a mutation in the HFE gene. We demonstrated that the rate of radiolabeled iron (59Fe) uptake was similar between the two genotypes despite higher brain iron concentrations in the mutant. However, there were significant differences in iron uptake between males and females regardless of genotype. These data indicate that brain iron status is consistently maintained and tightly regulated at the level of the blood-brain barrier.
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Affiliation(s)
- Kari A Duck
- Department of Neurosurgery, Penn State Hershey Medical Center, Hershey, PA, USA
| | - Elizabeth B Neely
- Department of Neurosurgery, Penn State Hershey Medical Center, Hershey, PA, USA
| | - Ian A Simpson
- Department of Neural and Behavioral Sciences, Penn State Hershey Medical Center, Hershey, PA, USA
| | - James R Connor
- Department of Neurosurgery, Penn State Hershey Medical Center, Hershey, PA, USA
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49
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Gerhard GS, Paynton BV, DiStefano JK. Identification of Genes for Hereditary Hemochromatosis. Methods Mol Biol 2018; 1706:353-365. [PMID: 29423808 DOI: 10.1007/978-1-4939-7471-9_19] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hereditary hemochromatosis (HH) is one of the most common genetically transmitted conditions in individuals of Northern European ancestry. The disease is characterized by excessive intestinal absorption of dietary iron, resulting in pathologically high iron storage in tissues and organs. If left untreated, HH can damage joints and organs, and eventually lead to death. There are four main classes of HH, as well as five individual molecular subtypes, caused by mutations in five genes, and the approaches implemented in the discovery of each HH type have specific histories and unique aspects. In this chapter, we review the genetics of the different HH types, including the strategies used to detect the causal variants in each case and the manner in which genetic variants were found to affect iron metabolism.
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Affiliation(s)
- Glenn S Gerhard
- Department of Medical Genetics and Molecular Biochemistry, 960 Medical Education and Research Building (MERB), Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA, 19140, USA.
| | - Barbara V Paynton
- Department of Medical Genetics and Molecular Biology, The Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
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50
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Knutson MD. Iron transport proteins: Gateways of cellular and systemic iron homeostasis. J Biol Chem 2017; 292:12735-12743. [PMID: 28615441 DOI: 10.1074/jbc.r117.786632] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Cellular iron homeostasis is maintained by iron and heme transport proteins that work in concert with ferrireductases, ferroxidases, and chaperones to direct the movement of iron into, within, and out of cells. Systemic iron homeostasis is regulated by the liver-derived peptide hormone, hepcidin. The interface between cellular and systemic iron homeostasis is readily observed in the highly dynamic iron handling of four main cell types: duodenal enterocytes, erythrocyte precursors, macrophages, and hepatocytes. This review provides an overview of how these cell types handle iron, highlighting how iron and heme transporters mediate the exchange and distribution of body iron in health and disease.
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Affiliation(s)
- Mitchell D Knutson
- Food Science and Human Nutrition Department, University of Florida, Gainesville, Florida 32611-03170.
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